Vanilloid receptor ligands and their use in treatments

ABSTRACT

Substituted pyridines and pyrimidines and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.

This application claims the benefit of U.S. Provisional Application No.60/609,718, filed Sep. 13, 2004, which is hereby incorporated byreference.

BACKGROUND

The vanilloid receptor 1 (VR1) is the molecular target of capsaicin, theactive ingredient in hot peppers. Julius et al. reported the molecularcloning of VR1 (Caterina et al., 1997). VR1 is a non-selective cationchannel which is activated or sensitized by a series of differentstimuli including capsaicin and resiniferatoxin (exogenous activators),heat & acid stimulation and products of lipid bilayer metabolism,anandamide (Premkumar et al., 2000, Szabo et al., 2000, Gauldie et al.,2001, Olah et al., 2001) and lipoxygenase metabolites (Hwang et al.,2000). VR1 is highly expressed in primary sensory neurons (Caterina etal., 1997) in rats, mice and humans (Onozawa et al., 2000, Mezey et al.,2000, Helliwell et al., 1998, Cortright et al., 2001). These sensoryneurons innervate many visceral organs including the dermis, bones,bladder, gastrointestinal tract and lungs; VR1 is also expressed inother neuronal and non-neuronal tissues including but not limited to,CNS nuclei, kidney, stomach and T-cells (Nozawa et al., 2001, Yiangou etal., 2001, Birder et al., 2001). Presumably expression in these variouscells and organs may contribute to their basic properties such ascellular signaling and cell division.

Prior to the molecular cloning of VR1, experimentation with capsaicinindicated the presence of a capsaicin sensitive receptor, which couldincrease the activity of sensory neurons in humans, rats and mice(Holzer, 1991; Dray, 1992, Szallasi and Blumberg 1996, 1999). Theresults of acute activation by capsaicin in humans was pain at injectionsite and in other species increased behavioral sensitivity to sensorystimuli (Szallasi and Blumberg, 1999). Capsaicin application to the skinin humans causes a painful reaction characterized not only by theperception of heat and pain at the site of administration but also by awider area of hyperalgesia and allodynia, two characteristic symptoms ofthe human condition of neuropathic pain (Holzer, 1991). Taken together,it seems likely that increased activity of VR1 plays a significant rolein the establishment and maintenance of pain conditions. Topical orintradermal injection of capsaicin has also been shown to producelocalized vasodilation and edema production (Szallasi and Blumberg 1999,Singh et al., 2001). This evidence indicates that capsaicin through it'sactivation of VR1 can regulate afferent and efferent function of sensorynerves. Sensory nerve involvement in diseases could therefore bemodified by molecules which effect the function of the vanilloidreceptor to increase or decrease the activity of sensory nerves.

VR1 gene knockout mice have been shown to have reduced sensorysensitivity to thermal and acid stimuli (Caterina et al., 2000)). Thissupports the concept that VR1 contributes not only to generation of painresponses (i.e. via thermal, acid or capsaicin stimuli) but also to themaintenance of basal activity of sensory nerves. This evidence agreeswith studies demonstrating capsaicin sensitive nerve involvement indisease. Primary sensory nerves in humans and other species can be madeinactive by continued capsaicin stimulation. This paradigm causesreceptor activation induced desensitization of the primary sensorynerve—such reduction in sensory nerve activity in vivo makes subjectsless sensitive to subsequent painful stimuli. In this regard bothcapsaicin and resinferatoxin (exogenous activators of VR1), producedesensitization and they have been used for many proof of conceptstudies in in vivo models of disease (Holzer, 1991, Dray 1992, Szallasiand Blumberg 1999).

Bibliography

-   Birder-L A. Kanai-A J. de-Groat-W C. Kiss-S. Nealen-M L. Burke-N E.    Dineley-K E. Watkins-S. Reynolds-I J. Caterina-M J. (2001) Vanilloid    receptor expression suggests a sensory role for urinary bladder    epithelial cells. PNAS 98: 23: 13396-13401.-   Caterina, M. J, Schumacher, M. A., Tominaga, M., Rosen, T. A.,    Levine, J. D., and Julius, D, (1997). The capsaicin receptor: a    heat-activated ion channel in the pain pathway. Nature 389: 816-824.-   Caterina-M J. Leffler-A. Malmberg-A B. Martin-W J. Trafton-J.    Petersen-Zeitz K R. Koltzenburg-M. Basbaum-A I. Julius-D (2000)    Impaired nociception and pain sensation in mice lacking the    capsaicin receptor. Science—(Washington, D.C.). 288: 5464: 306-313.-   Cortright-D N. Crandall-M. Sanchez-J F. Zou-T. Krause-J E.-   White-G (2001) The tissue distribution and functional    characterization of human VR1. Biochemical and Biophysical Research    Communications 281: 5: 1183-1189-   Dray, A., (1992). Therapeutic potential of capsaicin-like molecules.    Life Sciences 51: 1759-1765.-   Gauldie-S D. McQueen-D S. Pertwee-R. Chessell-I P. (2001) Anandamide    activates peripheral nociceptors in normal and arthritic rat knee    joints. British Journal of Pharmacology 132: 3: 617-621.-   Helliwell-R J A. McLatchie-L M. Clarke-M. Winter-J. Bevan-S.    McIntyre-P (1998) Capsaicin sensitivity is associated with    expression of the vanilloid (capsaicin) receptor (VR1) mRNA in adult    rat sensory ganglia. Neuroscience Lett. 250: 3: 177-180.-   Holzer, P. (1991) Capsaicin: Cellular targets, Mechanisms of Action    and selectivity for thin sensory neurons. Pharmacological reviews    43: 2: 143-201-   Hwang-S W. Cho-H. Kwak-J. Lee-S Y. Kang-C J. Jung-J. Cho-S.-   Min-K H. Suh-Y G. Kim-D. Oh-U. (2000) Direct activation of capsaicin    receptors by products of lipoxygenases: Endogenous capsaicin-like    substances. PNAS 97: 11: 6155-6160.-   Mezey-E. Toth-Z E. Cortright-D N. Arzubi-M K. Krause-J E. Elde-R.    Guo-A. Blumberg-P M. Szallasi-A (2000) Distribution of mRNA for    vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity,    in the central nervous system of the rat and human. PNAS 97: 7:    3655-3660.-   Nozawa-Y. Nishihara-K. Yamamoto-A. Nakano-M. Ajioka-H.    Matsuura-N. (2001) Distribution and characterization of vanilloid    receptors in the rat stomach. Neuroscience Letters 309: 1: 33-36.-   Olah-Z. Karai-L. Iadarola-M J. (2001) Anandamide activates vanilloid    receptor 1 (VR1) at acidic pH in dorsal root ganglia neurons and    cells ectopically expressing VR1. Journal of Biological Chemistry    276: 33, 31163-31170.-   Onozawa-K. Nakamura-A. Tsutsumi-S. Yao-J. Ishikawa-R.    Kohama-K. (2000) Tissue distribution of capsaicin receptor in the    various organs of rats. Proc. Jpn. Acad. Ser. B, Phys.-Biol. Sci.    76: 5: 68-72.-   Premkumar-L S. Ahern-G P. (2000) Induction of vanilloid receptor    channel activity by protein kinase C. Nature (London) 408: 6815:    985-990.-   Singh-L K. Pang-X. Alexacos-N. Letourneau-R. Theoharides-T C. (1999)    Acute immobilization stress triggers skin mast cell degranulation    via corticotropin releasing hormone, neurotensin, and substance P: A    link to neurogenic skin disorders. Brain Behav. Immun. 13: 3:    225-239.-   Szallasi, A. Blumberg-P M (1996) Vanilloid receptors: New insights    enhance potential as a therapeutic target. Pain 68: 195-208-   Szallasi-A. Blumberg-P M. (1999) Vanilloid (capsaicin) receptors and    mechanisms. Pharmacol. Rev. 51: 2: 159-211.

Szabo-T. Wang-J. Gonzalez-A. Kedei-N. Lile-J. Treanor-J. Blumberg-P M.(2000) Pharmacological characterization of the human vanilloid receptortype-1 (hVR1). Society for Neuroscience Abstracts. 26:1-2: 634.18.

-   Tominaga, M., Caterina, M. J., Malmberg, A. B., Rosen, T. A.,    Gilbert, H., Skinner, K., Raumann, B. E., Basbaum, A. I., and    Julius, D., (1998). The cloned capsaicin receptor integrates    multiple pain-producing stimuli. Neuron 21: 531-543.-   Yiangou-Y. Facer-P. Dyer-N H C. Chan-C L H. Knowles-C. Williams-N S.    Anand-P. (2001) Vanilloid receptor 1 immunoreactivity in inflamed    human bowel. Lancet (North American Edition) 357: 9265: 1338-1339.-   Yiangou-Y. Facer-P. Ford-A. Brady-C. Wiseman-O. Fowler-C J.    Anand-P. (2001) Capsaicin receptor VR1 and ATP-gated ion channel    P2X3 in human urinary bladder. BJU International 87: 9: 774-779.-   Wang-H. Bian-D. Zhu-D. Zajic-G. Loeloff-R. Lile-J. Wild-K.    Treanor-J. Curran-E. (2000) Inflammation-induced upregulation of VR1    in rat spinal cord and DRG correlates with enhanced nociceptive    processing. Society for Neuroscience Abstracts 26:1-2: 632.15.

SUMMARY

The present invention comprises a new class of compounds useful in thetreatment of diseases, such as vanilloid-receptor-mediated diseases andother maladies, such as inflammatory or neuropathic pain and diseasesinvolving sensory nerve function such as asthma, rheumatoid arthritis,osteoarthritis, inflammatory bowel disorders, urinary incontinence,migraine and psoriasis. In particular, the compounds of the inventionare useful for the treatment of acute, inflammatory and neuropathicpain, dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, inflammatory eye disorders, inflammatoryor unstable bladder disorders, psoriasis, skin complaints withinflammatory components, chronic inflammatory conditions, inflammatorypain and associated hyperalgesia and allodynia, neuropathic pain andassociated hyperalgesia and allodynia, diabetic neuropathy pain,causalgia, sympathetically maintained pain, deafferentation syndromes,asthma, epithelial tissue damage or dysfunction, herpes simplex,disturbances of visceral motility at respiratory, genitourinary,gastrointestinal or vascular regions, wounds, burns, allergic skinreactions, pruritus, vitiligo, general gastrointestinal disorders,gastric ulceration, duodenal ulcers, diarrhea, gastric lesions inducedby necrotising agents, hair growth, vasomotor or allergic rhinitis,bronchial disorders or bladder disorders. Accordingly, the inventionalso comprises pharmaceutical compositions comprising the compounds,methods for the treatment of vanilloid-receptor-mediated diseases, suchas inflammatory or neuropathic pain, asthma, rheumatoid arthritis,osteoarthritis, inflammatory bowel disorders, urinary incontinence,migraine and psoriasis diseases, using the compounds and compositions ofthe invention, and intermediates and processes useful for thepreparation of the compounds of the invention.

The compounds of the invention are represented by the following generalstructure:

or a pharmaceutically acceptable salt thereof, wherein J, R¹, R³, R⁴,R⁵, X and Y are defined below.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way. All patents, patent applications and other publications recitedherein are hereby incorporated by reference in their entirety.

DETAILED DESCRIPTION

One aspect of the current invention relates to compounds having thegeneral structure:

or any pharmaceutically-acceptable salt or hydrate thereof, wherein:

J is NH, O or S;

X is N or C(R²);

Y is N or C(R²), wherein at least one of X and Y is N;

n is independently, at each instance, 0, 1 or 2;

R¹ is a saturated, partially saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, whereinthe available carbon atoms of the ring are substituted by 0, 1 or 2 oxoor thioxo groups, wherein the ring is substituted by 1, 2 or 3substituents independently selected from R^(e), R^(g), R^(c), halo,nitro, cyano, R^(i), —OR^(i), —OC₂₋₆alkylNR^(a)R^(i), —OC₂₋₆alkylOR^(i),—NR^(a)R^(i), —NR^(f)C₂₋₆alkylNR^(a)R^(i), —NR^(f)C₂₋₆alkylOR^(i),—CO₂R^(i), —C(═O)R^(i), —C(═O)NR^(a)R^(i), —NR^(f)C(═O)R^(i),—NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i), —C₁₋₈alkylOR^(i),—C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i), —S(═O)₂NR^(a)R^(i),—NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(e), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I;

R² is, independently, in each instance, R^(d), halo, C₁₋₈alkylsubstituted by 0, 1 or 2 substituents selected from R^(d), halo,—(CH₂)_(n)phenyl substituted by 0, 1, 2 or 3 substituents independentlyselected from R^(d) and halo, or a saturated, partially saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3heteroatoms independently selected from N, O and S, wherein no more than2 of the ring members are O or S, wherein the heterocycle is optionallyfused with a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents independently selected fromR^(d) and halo;

R³ is

-   -   (A) C₁₋₈alkyl substituted by 1, 2 or 3 substituents        independently selected from halo, nitro, cyano, —OR^(i),        —OC₂₋₆alkylNR^(a)R^(i), —OC₂₋₆alkylOR^(i), —NR^(a)R^(i),        —NR^(f)C₂₋₆alkylNR^(a)R^(i), —NR^(f)C₂₋₆alkylOR^(i), —CO₂R^(i),        —C(═O)R^(i), —C(═O)NR^(a)R^(i), —NR^(f)C(═O)R^(i),        —NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i), —C₁₋₈alkylOR^(i),        —C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i), —S(═O)₂NR^(a)R^(i),        —NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(f), —OR^(g),        —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f),        —NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f),        —NR^(f)C₂₋₆alkylOR^(f), —CO₂R^(e), —C(═O)R^(e),        —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g), —NR^(f)C(═O)R^(e),        —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e),        —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e),        —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and —OC(═O)NR^(a)R^(f),        and additionally substituted by 0, 1 or 2 R^(i) groups, and        additionally substituted by 0, 1, 2, 3, 4 or 5 substituents        independently selected from Br, Cl, F and I; or    -   (B) a saturated, partially saturated or unsaturated 5-, 6- or        7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered        bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N,        O and S, wherein the available carbon atoms of the ring are        substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring        is substituted by 0, 1, 2 or 3 substituents independently        selected from R^(e), R^(h), halo, nitro, cyano, —OR^(e),        —OR^(g), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),        —NR^(a)R^(f), —NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f),        —NR^(f)C₂₋₆alkylOR^(f), naphthyl, —CO₂R^(e), —C(═O)R^(e),        —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g), —NR^(f)C(═O)R^(e),        —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e),        —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e),        —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and —OC(═O)NR^(a)R^(f),        and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5        substituents independently selected from Br, Cl, F and I; or    -   (C) —N(R^(a))—C₁₋₈alkyl, wherein the C₁₋₈alkyl is substituted by        1, 2 or 3 substituents independently selected from R^(h), halo,        nitro, cyano, R^(i), —OR^(i), —OC₂₋₆alkylNR^(a)R^(i),        —OC₂₋₆alkylOR^(i), —NR^(a)R^(i), —NR^(f)C₂₋₆alkylNR^(a)R^(i),        —NR^(f)C₂₋₆alkylOR^(i), —CO₂R^(i), —C(═O)R^(i),        —C(═O)NR^(a)R^(i), —NR^(f)C(═O)R^(i), —NR^(f)C(═O)NR^(a)R^(i),        —NR^(f)CO₂R^(i), —C₁₋₈alkylOR¹, —C₁₋₆alkylNR^(a)R^(i),        —S(═O)_(n)R^(i), —S(═O)₂NR^(a)R^(i), —NR^(a)S(═O)₂R^(i),        —OC(═O)NR^(a)R^(i), —OR^(e), —OR^(g), —OC₂₋₆alkylNR^(a)R^(f),        —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),        —NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,        —CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),        —NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),        —NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),        —S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and        —OC(═O)NR^(a)R^(f), and additionally substituted by 0, 1, 2, 3,        4 or 5 substituents independently selected from Br, Cl, F and I;        or    -   (D) —OC₁₋₈alkyl, wherein the C₁₋₈alkyl is substituted by 1, 2 or        3 substituents independently selected from R^(e), R^(h), halo,        nitro, cyano, R^(i), —OR^(i), —OC₂₋₆alkylNR^(a)R^(i),        —OC₂₋₆alkylOR^(i), —NR^(a)R^(i), —NR^(f)C₂₋₆alkylNR^(a)R^(i),        —NR^(f)C₂₋₆alkylOR_(i), —CO₂R^(i), —C(═O)R^(i),        —C(═O)NR^(a)R^(i), —NR^(f)C(═O)R^(i), —NR^(f)C(═O)NR^(a)R^(i),        —NR^(f)CO₂R^(i), —C₁₋₈alkylOR^(i), —C₁₋₆alkylNR^(a)R^(i),        —S(═O)_(n)R^(i), —S(═O)₂NR^(a)R^(i), —NR^(a)S(═O)₂R^(i),        —OC(═O)NR^(a)R^(i), —OR^(e), —OC₂₋₆alkylNR^(a)R^(f),        —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),        —NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,        —CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),        —NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),        —NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),        —S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and        —OC(═O)NR^(a)R^(f), and additionally substituted by 0, 1, 2, 3,        4 or 5 substituents independently selected from Br, Cl, F and I;        or    -   (E) C₄₋₈alkyl, cyano, —OC₃₋₈alkyl, —OR^(i), —SR^(i),        —N(R^(a))R^(i), —NHC₄₋₈alkyl, or —N(C₁₋₈alkyl)C₄₋₈alkyl;

R⁴ is a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0,1, 2, 3 or 4 atoms selected from N, O and S, wherein the availablecarbon atoms of the ring are substituted by 0, 1 or 2 oxo or thioxogroups, wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(f), R^(g), R^(c), nitro, cyano, —OR^(e),—OR^(g), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f),—NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f),naphthyl, —CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I;wherein R⁴ is not indazolyl;

R⁵ is H or CH₃;

R^(a) is independently, at each instance, H or R^(b);

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alkyl,the phenyl, benzyl and C₁₋₆alkyl being substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OC₁₋₄alkyl,—NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl;

R^(c) is independently, in each instance, phenyl substituted by 0, 1 or2 groups selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(a) and—NR^(a)R^(a); or R^(c) is a saturated, partially saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3heteroatoms independently selected from N, O and S, wherein no more than2 of the ring members are O or S, wherein the heterocycle is optionallyfused with a phenyl ring, and the carbon atoms of the heterocycle aresubstituted by 0, 1 or 2 oxo or thioxo or thioxo groups, wherein theheterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(a) and—NR^(a)R^(a);

R^(d) is independently in each instance selected from H, C₁₋₅alkyl,C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R^(d) is a saturated, partially saturated orunsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or11-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, Oand S, wherein there are no more than 2 N atoms, wherein the ring issubstituted by 0, 1 or 2 oxo or thioxo or thioxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from R^(e), halo,cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R_(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R^(d) is C₁₋₄alkyl substituted by 0, 1, 2 or3 groups selected from C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(e),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂ ₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h), —N^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h);

R^(e) is, independently, in each instance, C₁₋₉alkyl orC₁₋₄alkyl(phenyl) wherein either is substituted by 0, 1, 2, 3 or 4substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆, OR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); and wherein theC₁₋₉alkyl is additionally substituted by 0 or 1 groups independentlyselected from R^(h) and additionally substituted by 0, 1, 2, 3, 4 or 5substituents independently selected from Br, Cl, F and I;

R^(f) is, independently, in each instance, R^(e) or H;

R^(g) is, independently, in each instance, a saturated, partiallysaturated or unsaturated 5- or 6-membered monocyclic ring containing 1,2 or 3 atoms selected from N, O and S, so long as the combination of Oand S atoms is not greater than 2, wherein the ring is substituted by 0or 1 oxo or thioxo groups;

R^(h) is, independently, in each instance, phenyl or a saturated,partially saturated or unsaturated 5- or 6-membered monocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S, so long as thecombination of O and S atoms is not greater than 2, wherein the ring issubstituted by 0 or 1 oxo or thioxo groups, wherein the phenyl ormonocycle are substituted by 0, 1, 2 or 3 substituents selected fromhalo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(f), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(e),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(e), —(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f) and—NR^(a)C₂₋₆alkylOR^(f); and

R^(i) is a saturated, partially saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, whereinthe available carbon atoms of the ring are substituted by 0, 1 or 2 oxoor thioxo groups, wherein the ring is substituted by 0, 1, 2 or 3substituents independently selected from R^(f), R^(g), R^(c), halo,nitro, cyano, —OR^(e), —OR^(g), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(e), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is a heterocycle selected from the group ofthiophene, pyrrole, 1,3-oxazole, 1,3-thiazol-4-yl, 1,3,4-oxadiazole,1,3,4-thiadiazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole,1H-1,2,3-triazole, isothiazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole,1,2,3,4-oxatriazole, 1,2,3,4-thiatriazole, 1H-1,2,3,4-tetraazole,1,2,3,5-oxatriazole, 1,2,3,5-thiatriazole, furan, imidazol-2-yl,benzimidazole, 1,2,4-triazole, isoxazole, pyrazol-3-yl, pyrazol-4-yl,pyrazol-5-yl, thiolane, pyrrolidine, tetrahydrofuran,4,5-dihydrothiophene, 2-pyrroline, 4,5-dihydrofuran, pyridazine,pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine,pyridine, 2H-3,4,5,6-tetrahydropyran, thiane, 1,2-diazaperhydroine,1,3-diazaperhydroine, piperazine, 1,3-oxazaperhydroine, morpholine,1,3-thiazaperhydroine, 1,4-thiazaperhydroine, piperidine,2H-3,4-dihydropyran, 2,3-dihydro-4H-thiin, 1,4,5,6-tetrahydropyridine,2H-5,6-dihydropyran, 2,3-dihydro-6H-thiin, 1,2,5,6-tetrahydropyridine,3,4,5,6-tetrahydropyridine, 4H-pyran, 4H-thiin, 1,4-dihydropyridine,1,4-dithiane, 1,4-dioxane, 1,4-oxathiane, 1,2-oxazolidine,1,2-thiazolidine, pyrazolidine, 1,3-oxazolidine, 1,3-thiazolidine,imidazolidine, 1,2,4-oxadiazolidine, 1,3,4-oxadiazolidine,1,2,4-thiadiazolidine, 1,3,4-thiadiazolidine, 1,2,4-triazolidine,2-imidazolin-1-yl, 2-imidazolin-2-yl, 3-imidazoline, 2-pyrazoline,4-imidazoline, 2,3-dihydroisothiazole, 4,5-dihydroisoxazole,4,5-dihydroisothiazole, 2,5-dihydroisoxazole, 2,5-dihydroisothiazole,2,3-dihydroisoxazole, 4,5-dihydrooxazole, 2,3-dihydrooxazole,2,5-dihydrooxazole, 4,5-dihydrothiazole, 2,3-dihydrothiazole,2,5-dihydrothiazole, 1,3,4-oxathiazolidine, 1,4,2-oxathiazolidine,2,3-dihydro-1H-[1,2,3]triazole, 2,5-dihydro-1H-[1,2,3]triazole,4,5-dihydro-1H-[1,2,3]triazol-1-yl, 4,5-dihydro-1H-[1,2,3]triazol-3-yl,4,5-dihydro-1H-[1,2,3]triazol-5-yl, 2,3-dihydro-1H-[1,2,4]triazole,4,5-dihydro-1H-[1,2,4]triazole, 2,3-dihydro-[1,2,4]oxadiazole,2,5-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]thiadiazole,2,3-dihydro-[1,2,4]thiadiazole, 2,5-dihydro-[1,2,4]thiadiazole,4,5-dihydro-[1,2,4]thiadiazole, 2,5-dihydro-[1,2,4]oxadiazole,2,3-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]oxadiazole,2,5-dihydro-[1,2,4]thiadiazole, 2,3-dihydro-[1,2,4]thiadiazole,4,5-dihydro-[1,2,4]thiadiazole, 2,3-dihydro-[1,3,4]oxadiazole,2,3-dihydro-[1,3,4]thiadiazole, [1,4,2]oxathiazole, [1,3,4]oxathiazole,1,3,5-triazaperhydroine, 1,2,4-triazaperhydroine,1,4,2-dithiazaperhydroine, 1,4,2-dioxazaperhydroine,1,3,5-oxadiazaperhydroine, 1,2,5-oxadiazaperhydroine,1,3,4-thiadiazaperhydroine, 1,3,5-thiadiazaperhydroine,1,2,5-thiadiazaperhydroine, 1,3,4-oxadiazaperhydroine,1,4,3-oxathiazaperhydroine, 1,4,2-oxathiazaperhydroine,1,4,5,6-tetrahydropyridazine, 1,2,3,4-tetrahydropyridazine,1,2,3,6-tetrahydropyridazine, 1,2,5,6-tetrahydropyrimidine,1,2,3,4-tetrahydropyrimidine, 1,4,5,6-tetrahydropyrimidine,1,2,3,6-tetrahydropyrazine, 1,2,3,4-tetrahydropyrazine,5,6-dihydro-4H-[1,2]oxazine, 5,6-dihydro-2H-[1,2]oxazine,3,6-dihydro-2H-[1,2]oxazine, 3,4-dihydro-2H-[1,2]oxazine,5,6-dihydro-4H-[1,2]thiazine, 5,6-dihydro-2H-[1,2]thiazine,3,6-dihydro-2H-[1,2]thiazine, 3,4-dihydro-2H-[1,2]thiazine,5,6-dihydro-2H-[1,3]oxazine, 5,6-dihydro-4H-[1,3]oxazine,3,6-dihydro-2H-[1,3]oxazine, 3,4-dihydro-2H-[1,3]oxazine,3,6-dihydro-2H-[1,4]oxazine, 3,4-dihydro-2H-[1,4]oxazine,5,6-dihydro-2H-[1,3]thiazine, 5,6-dihydro-4H-[1,3]thiazine,3,6-dihydro-2H-[1,3]thiazine, 3,4-dihydro-2H-[1,3]thiazine,3,6-dihydro-2H-[1,4]thiazine, 3,4-dihydro-2H-[1,4]thiazine,1,2,3,6-tetrahydro-[1,2,4]triazine, 1,2,3,4-tetrahydro-[1,2,4]triazine,1,2,3,4-tetrahydro-[1,3,5]triazine, 2,3,4,5-tetrahydro-[1,2,4]triazine,1,4,5,6-tetrahydro-[1,2,4]triazine, 5,6-dihydro-[1,4,2]dioxazine,5,6-dihydro-[1,4,2]dithiazine, 2,3-dihydro-[1,4,2]dioxazine,3,4-dihydro-2H-[1,3,4]oxadiazine, 3,6-dihydro-2H-[1,3,4]oxadiazine,3,4-dihydro-2H-[1,3,5]oxadiazine, 3,6-dihydro-2H-[1,3,5]oxadiazine,5,6-dihydro-2H-[1,2,5]oxadiazine, 5,6-dihydro-4H-[1,2,5]oxadiazine,3,4-dihydro-2H-[1,3,4]thiadiazine, 3,6-dihydro-2H-[1,3,4]thiadiazine,3,4-dihydro-2H-[1,3,5]thiadiazine, 3,6-dihydro-2H-[1,3,5]thiadiazine,5,6-dihydro-2H-[1,2,5]thiadiazine, 5,6-dihydro-4H-[1,2,5]thiadiazine,5,6-dihydro-2H-[1,2,3]oxadiazine, 3,6-dihydro-2H-[1,2,5]oxadiazine,5,6-dihydro-4H-[1,3,4]oxadiazine, 3,4-dihydro-2H-[1,2,5]oxadiazine,5,6-dihydro-2H-[1,2,3]thiadiazine, 3,6-dihydro-2H-[1,2,5]thiadiazine,5,6-dihydro-4H-[1,3,4]thiadiazine, 3,4-dihydro-2H-[1,2,5]thiadiazine,5,6-dihydro-[1,4,3]oxathiazine, 5,6-dihydro-[1,4,2]oxathiazine,2,3-dihydro-[1,4,3]oxathiazine, 2,3-dihydro-[1,4,2]oxathiazine,3,4-dihydropyridine, 1,2-dihydropyridine, 5,6-dihydropyridine, 2H-pyran,2H-thiin, 3,6-dihydropyridine, 2,3-dihydropyridazine,2,5-dihydropyridazine, 4,5-dihydropyridazine, 1,2-dihydropyridazine,1,4-dihydropyrimidin-1-yl, 1,4-dihydropyrimidin-4-yl,1,4-dihydropyrimidin-5-yl, 1,4-dihydropyrimidin-6-yl,2,3-dihydropyrimidine, 2,5-dihydropyrimidine, 5,6-dihydropyrimidine,3,6-dihydropyrimidine, 5,6-dihydropyrazine, 3,6-dihydropyrazine,4,5-dihydropyrazine, 1,4-dihydropyrazine, 1,4-dithiin, 1,4-dioxin,2H-1,2-oxazine, 6H-1,2-oxazine, 4H-1,2-oxazine, 2H-1,3-oxazine,4H-1,3-oxazine, 6H-1,3-oxazine, 2H-1,4-oxazine, 4H-1,4-oxazine,2H-1,3-thiazine, 2H-1,4-thiazine, 4H-1,2-thiazine, 6H-1,3-thiazine,4H-1,4-thiazine, 2H-1,2-thiazine, 6H-1,2-thiazine, 1,4-oxathiin,2H,5H-1,2,3-triazine, 1H,4H-1,2,3-triazine, 4,5-dihydro-1,2,3-triazine,1H,6H-1,2,3-triazine, 1,2-dihydro-1,2,3-triazine,2,3-dihydro-1,2,4-triazine, 3H,6H-1,2,4-triazine, 1H,6H-1,2,4-triazine,3,4-dihydro-1,2,4-triazine, 1H,4H-1,2,4-triazine,5,6-dihydro-1,2,4-triazine, 4,5-dihydro-1,2,4-triazine,2H,5H-1,2,4-triazine, 1,2-dihydro-1,2,4-triazine, 1H,4H-1,3,5-triazine,1,2-dihydro-1,3,5-triazine, 1,4,2-dithiazine, 1,4,2-dioxazine,2H-1,3,4-oxadiazine, 2H-1,3,5-oxadiazine, 6H-1,2,5-oxadiazine,4H-1,3,4-oxadiazine, 4H-1,3,5-oxadiazine, 4H-1,2,5-oxadiazine,2H-1,3,5-thiadiazine, 6H-1,2,5-thiadiazine, 4H-1,3,4-thiadiazine,4H-1,3,5-thiadiazine, 4H-1,2,5-thiadiazine, 2H-1,3,4-thiadiazine,6H-1,3,4-thiadiazine, 6H-1,3,4-oxadiazine, and 1,4,2-oxathiazine,wherein the heterocycle is optionally vicinally fused with a saturated,partially saturated or unsaturated 5-, 6- or 7-membered ring containing0, 1 or 2 atoms independently selected from N, O and S; wherein any ofthe heterocycles are substituted by 1, 2 or 3 substituents independentlyselected from R^(f), R^(g), R^(c), nitro, cyano, —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I;

In one embodiment, in conjunction with any one of the above and belowembodiments, J is NH or O.

In one embodiment, in conjunction with any one of the above and belowembodiments, J is NH.

In one embodiment, in conjunction with any one of the above and belowembodiments, J is O.

In another embodiment, in conjunction with any one of the above andbelow embodiments, X is N and Y is N.

In another embodiment, in conjunction with any one of the above andbelow embodiments, X is C(R²) and Y is N.

In another embodiment, in conjunction with any one of the above andbelow embodiments, X is N and Y is C(R²).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is phenyl substituted by 1, 2 or 3 substituentsindependently selected from R^(f), R^(g), R^(c), halo, nitro, cyano,R^(i), —OR^(i), —OC₂₋₆alkylNR^(a)R^(i), —OC₂₋₆alkylOR^(i), —NR^(a)R^(i),—NR^(f)C₂₋₆-alkylNR^(a)R^(i), —NR^(f)C₂₋₆alkylOR^(i), —CO₂R^(i),—C(═O)R^(i), —C(═O)NR^(a)R^(i), —NR^(f)C(═O)R^(i),—NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i), —C₁₋₈alkylOR^(i),—C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i), —S(═O)₂NR^(a)R^(i),—NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(e), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the phenyl is additionally substituted by 0, 1or 2 substituents independently selected from Br, Cl, F and I.

EMBODIMENT A

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is phenyl substituted in the 4-position by asubstituent selected from R^(f), halo, or —OR^(e), and the phenyl isfurther substituted by 0, 1 or 2 substituents independently selectedfrom R^(f), R^(g), R^(c), halo, nitro, cyano, R^(i), —OR^(i),—OC₂₋₆alkylNR^(a)R^(i), —OC₂₋₆alkylOR^(i), —NR^(a)R^(i),—NR^(f)C₂₋₆alkylNR^(a)R^(i), —NR^(f)C₂₋₆alkylOR^(i), —CO₂R^(i),—C(═O)R^(i), —C(═O)NR^(a)R^(i), —NR^(f)C(═O)R^(i),—NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i), —C₁₋₈alkylOR^(i),—C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i), —S(═O)₂NR^(a)R^(i),—NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR_(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(e), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the phenyl is additionally substituted by 0, 1or 2 substituents independently selected from Br, Cl, F and I.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is phenyl substituted in the 4-position by asubstituent selected from C₂₋₅alkyl or C₁₋₂haloalkyl and the phenyl isfurther substituted by 0, 1 or 2 substituents independently selectedfrom R^(f), R^(g), R^(c), halo, nitro, cyano, R^(i), —OR^(i),—OC₂₋₆alkylNR^(a)R^(i), —OC₂₋₆alkylOR^(i), —NR^(a)R^(i),—NR^(f)C₂₋₆alkylNR^(a)R^(i), —NR^(f)C₂₋₆alkylOR^(i), —CO₂R^(i),—C(═O)R^(i), —C(═O)NR^(a)R^(i), —NR^(f)C(═O)R^(i),—NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i), —C₁₋₈alkylOR^(i),—C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i), —S(═O)₂NR^(a)R^(i),—NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(e), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the phenyl is additionally substituted by 0, 1or 2 substituents independently selected from Br, Cl, F and I.

EMBODIMENT B

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is an unsaturated 5-, 6- or 7-membered monocyclicring containing 1, 2, 3 or 4 atoms selected from N, O and S, wherein theavailable carbon atoms of the ring are substituted by 0, 1 or 2 oxo orthioxo groups, wherein the ring is substituted by 1, 2 or 3 substituentsindependently selected from R^(f), R^(g), R^(c), nitro, cyano, R^(i),—OR^(i), —OC₂₋₆alkylNR^(a)R^(i), —OC₂₋₆alkylOR^(i), —NR^(a)R^(i),—NR^(f)C₂₋₆alkylNR^(a)R^(i), —NR^(f)C₂₋₆alkylOR^(i), —CO₂R^(i),—C(═O)R^(i), —C(═O)NR^(a)R^(i), —NR^(f)C(═O)R^(i),—NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i), —C₁₋₈alkylOR^(i),—C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i), —S(═)₂NR^(a)R^(i),—NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(e), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is an unsaturated 6-membered monocyclic ringcontaining 1 or 2 N atoms, wherein the ring is substituted by 1, 2 or 3substituents independently selected from R^(f), R^(g), R^(c), nitro,cyano, R^(i), —OR^(i), —OC₂₋₆alkylNR^(a)R^(i), —OC₂₋₆alkylOR^(i),—NR^(a)R^(i), —NR^(f)C₂₋₆alkylNR^(a)R^(i), —NR^(f)C₂₋₆alkylOR^(i),—CO₂R^(i), —C(═O)R^(i), —C(═O)NR^(a)R^(i), —NR^(f)C(═O)R^(i),—NR^(f)C(═O)NR^(a)R^(i), —NR_(f)CO₂R^(i), —C₁₋₈alkylOR^(i),—C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i), —S(═O)₂NR^(a)R^(i),—NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(e), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is an unsaturated 5-membered monocyclic ringcontaining 1 or 2 atoms selected from N, O and S, wherein the ring issubstituted by 1, 2 or 3 substituents independently selected from R^(f),R^(g), R^(c), nitro, cyano, R^(i), —OR^(i), —OC₂₋₆alkylNR^(a)R^(i),—OC₂₋₆alkylOR^(i), —NR^(a)R^(i), —NR^(f)C₂₋₆alkylNR^(a)R^(i),—NR^(f)C₂₋₆alkylOR^(i), —CO₂R^(i), —C(═O)R^(i), —C(═O)NR^(a)R^(i),—NR^(f)C(═O)R^(i), —NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i),—C₁₋₈alkylOR^(i), —C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i),—S(═O)₂NR^(a)R^(i), —NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(e),—OR^(g), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f),—NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f),naphthyl, —CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(e), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I.

EMBODIMENT C

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is a saturated or partially saturated 5-, 6- or7-membered monocyclic ring containing 1, 2, 3 or 4 atoms selected fromN, O and S, wherein the available carbon atoms of the ring aresubstituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring issubstituted by 1, 2 or 3 substituents independently selected from R^(f),R^(g), R^(c), nitro, cyano, R^(i), —OR^(i), —OC₂₋₆alkylNR^(a)R^(i),—OC₂₋₆alkylOR^(i), —NR^(a)R^(i), —NR^(f)C₂₋₆alkylNR^(a)R^(i),—NR^(f)C₂₋₆alkylOR^(i), —CO₂R^(i), —C(═O)R^(i), —C(═O)NR^(a)R^(i),—NR^(f)C(═O)R^(i), —NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i),—C₁₋₈alkylOR^(i), —C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i),—S(═O)₂NR^(a)R^(i), —NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(e),—OR^(g), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f),—NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f),naphthyl, —CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(e), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is a saturated or partially saturated 5-, 6- or7-membered monocyclic ring containing 1 or 2 atoms selected from N andO, wherein the available carbon atoms of the ring are substituted by 0,1 or 2 oxo or thioxo groups, wherein the ring is substituted by 1, 2 or3 substituents independently selected from R^(f), R^(g), R^(c), nitro,cyano, —OR^(e), —OR^(g), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—NR^(a)R^(f), —NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f),—NR^(f)C₂₋₆alkylOR^(f), naphthyl, —CO₂R^(e), —C(═O)R^(e),—C(═O)NR^(a)R^(e), —C(═O)NR^(a)R^(g), —NR^(f)C(═O)R^(e),—NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e),—C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e),—S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and —OC(═O)NR^(a)R^(f), and thering is additionally substituted by 0, 1, 2, 3, 4 or 5 substituentsindependently selected from Br, Cl, F and I.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is a saturated or partially saturated 6-memberedmonocyclic ring containing 1 or 2 N atoms, wherein the ring issubstituted by 1, 2 or 3 substituents independently selected from R^(f),R^(g), R^(c), nitro, cyano, R^(i), —OR^(i), —OC₂₋₆alkylNR^(a)R^(i),—OC₂₋₆alkylOR^(i), —NR^(a)R^(i), —NR^(f)C₂₋₆alkylNR^(a)R^(i),—NR^(f)C₂₋₆OR^(i), —CO₂R^(i), —C(═O)R^(i), —C(═O)NR^(a)R^(i),—NR^(f)C(═O)R^(i), —NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i),—C₁₋₈alkylOR^(i), —C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i),—S(═O)₂NR^(a)R^(i), —NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(e),—OR^(g), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f),—NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f),naphthyl, —CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(e), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is, independently, in each instance, H, halo,C₁₋₈alkyl substituted by 0, 1 or 2 substituents selected from R^(d) andhalo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is, independently, in each instance, halo,C₁₋₈alkyl substituted by 0, 1 or 2 substituents selected from R^(d),halo, —(CH₂)_(n)phenyl substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(d) and halo, or a saturated, partiallysaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein nomore than 2 of the ring members are O or S, wherein the heterocycle isoptionally fused with a phenyl ring, and the heterocycle or fused phenylring is substituted by 0, 1, 2 or 3 substituents independently selectedfrom R^(d) and halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is, independently, in each instance, H, halo,C₁₋₅alkyl, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R² is a saturated, partially saturated orunsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 1l-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, Oand S, wherein there are no more than 2 N atoms, wherein the ring issubstituted by 0, 1 or 2 oxo or thioxo or thioxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from R^(e), halo,cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R² is C₁₋₄alkyl substituted by 0, 1, 2 or 3groups selected from C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(e),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is, independently, in each instance, halo,C₁₋₅alkyl, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NC₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R² is a saturated, partially saturated orunsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or11-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, Oand S, wherein there are no more than 2 N atoms, wherein the ring issubstituted by 0, 1 or 2 oxo or thioxo or thioxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from R^(e), halo,cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR, —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R² is C₁₋₄alkyl substituted by 0, 1, 2 or 3groups selected from C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(e),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h).

EMBODIMENT D

In another embodiment, in conjunction with any one of the above andbelow embodiments, R³ is C₁₋₈alkyl substituted by 1, 2 or 3 substituentsindependently selected from halo, nitro, cyano, —OR^(i),—OC₂₋₆alkylNR^(a)R^(i), —OC₂₋₆alkylOR^(i), —NR^(a)R^(i),—NR^(f)C₂₋₆alkylNR^(a)R^(i), —NR^(f)C₂₋₆alkylOR^(i), —CO₂R^(i),—C(═O)R^(i), —C(═O)NR^(a)R^(i), —NR^(f)C(═O)R^(i),—NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i), —C₁₋₈alkylOR^(i),—C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i), —S(═O)₂NR^(a)R^(i),—NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(f), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), —CO₂R^(e),—C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g), —NR^(f)C(═O)R^(e),—NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e),—C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e),—S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and —OC(═O)NR^(a)R^(f), andadditionally substituted by 0, 1 or 2 R^(i) groups, and additionallysubstituted by 0, 1, 2, 3, 4 or 5 substituents independently selectedfrom Br, Cl, F and I.

EMBODIMENT E

In another embodiment, in conjunction with any one of the above andbelow embodiments, R³ is a saturated, partially saturated or unsaturated5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-memberedbicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S,wherein the available carbon atoms of the ring are substituted by 0, 1or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1, 2 or3 substituents independently selected from R^(e), R^(h), halo, nitro,cyano, —OR^(e), —OR^(g), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—NR^(a)R^(f), —NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f),—NR^(f)C₂₋₆alkylOR^(f), naphthyl, —CO₂R^(e), —C(═O)R^(e),—C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g), —NR^(f)C(═O)R^(e),—NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e),—C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e),—S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and —OC(═O)NR^(a)R^(f), and thering is additionally substituted by 0, 1, 2, 3, 4 or 5 substituentsindependently selected from Br, Cl, F and I.

EMBODIMENT F

In another embodiment, in conjunction with any one of the above andbelow embodiments, R³ is —N(R^(a))—C₁₋₈alkyl, wherein the C₁₋₈alkyl issubstituted by 1, 2 or 3 substituents independently selected from R^(h),halo, nitro, cyano, R^(i), —OR^(i), —OC₂₋₆alkylNR^(a)R^(i),—OC₂₋₆alkylOR^(i), —NR^(a)R^(i), —NR^(f)C₂₋₆alkylNR^(a)R^(i),—NR^(f)C₂₋₆alkylOR^(i), —CO₂R^(i), —C(═O)R^(i), —C(═O)NR^(a)R^(i),—NR^(f)C(═O)R^(i), —NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i),—C₁₋₈alkylOR^(i), —C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i),—S(═O)₂NR^(a)R^(i), —NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(e),—OR^(g), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f),—NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f),naphthyl, —CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and additionally substituted by 0, 1, 2, 3, 4 or 5substituents independently selected from Br, Cl, F and I.

EMBODIMENT G

In another embodiment, in conjunction with any one of the above andbelow embodiments, R³ is —OC₁₋₈alkyl, wherein the C₁₋₈alkyl issubstituted by 1, 2 or 3 substituents independently selected from R^(e),R^(h), halo, nitro, cyano, R^(i), —OR^(i), —OC₂₋₆alkylNR^(a)R^(i),—OC₂₋₆alkylOR^(i), —NR^(a)R^(i), —NR^(f)C₂₋₆alkylNR^(a)R^(i),—NR^(f)C₂₋₆alkylOR^(i), —CO₂R^(i), —C(═O)R^(i), —C(═O)NR^(a)R^(i),—NR^(f)C(═O)R^(i), —NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i),—C₁₋₈alkylOR^(i), —C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i),—S(═O)₂NR^(a)R^(i), —NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and additionally substituted by 0, 1, 2, 3, 4 or 5substituents independently selected from Br, Cl, F and I.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R³ is C₄₋₈alkyl, cyano, —OC₃₋₈alkyl, —OR^(i),—SR^(i), —N(R^(a))R^(i), —NHC₄₋₈alkyl, or —N(C₁₋₈alkyl)C₄₋₈alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is a saturated, partially saturated or unsaturated10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atomsselected from N, O and S, wherein the available carbon atoms of the ringare substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring issubstituted by 0, 1, 2 or 3 substituents independently selected fromR^(f), R^(g), R^(c), nitro, cyano, —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I.

EMBODIMENT H

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is an unsaturated 10-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 N atoms, wherein the ring is substituted by0, 1, 2 or 3 substituents independently selected from R^(f), R^(g),R^(c), nitro, cyano, —OR^(e), —OR^(g), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is an saturated or partially saturated 10-memberedbicyclic ring containing 0, 1, 2, 3 or 4 N atoms, wherein the ring issubstituted by 0, 1, 2 or 3 substituents independently selected fromR^(f), R^(g), R^(c), nitro, cyano, —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is an saturated or partially saturated 10-memberedbicyclic carbocyclic ring substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(f), R^(g), R^(c), nitro, cyano, —OR^(e),—OR^(g), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f),—NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f),naphthyl, —CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I.

EMBODIMENT I

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is naphthyl substituted by 0, 1, 2 or 3substituents independently selected from R^(f), R^(g), R^(c), nitro,cyano, —OR^(e), —OR^(g), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—NR^(a)R^(f), —NR^(a)R^(g), —NR^(f)C₂₋₆NR^(a)R^(f),—NR^(f)C₂₋₆alkylOR^(f), naphthyl, —CO₂R^(e), —C(═O)R^(e),—C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g), —NR^(f)C(═O)R^(e),—NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e),—C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e),—S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and —OC(═O)NR^(a)R^(f), and thering is additionally substituted by 0, 1, 2, 3, 4 or 5 substituentsindependently selected from Br, Cl, F and I.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is a saturated, partially saturated or unsaturated9-membered bicyclic ring containing 1, 2, 3 or 4 atoms selected from N,O and S, wherein the available carbon atoms of the ring are substitutedby 0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by 0,1, 2 or 3 substituents independently selected from R^(f), R^(g), R^(c),nitro, cyano, —OR^(e), —OR^(g), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I;wherein R⁴ is not indazolyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is a partially saturated or unsaturated 9-memberedbicyclic ring containing 1, 2, 3 or 4 atoms selected from N, O and S,wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(f), R^(g), R^(c), nitro, cyano, —OR^(e),—OR^(g), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f),—NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f),naphthyl, —CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I;wherein R⁴ is not indazolyl.

EMBODIMENT J

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is a partially saturated or unsaturated 9-memberedbicyclic ring containing 1 atom selected from O and S, and 1, 2 or 3 Natoms, wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(f), R^(g), R^(c), nitro, cyano, —OR^(e),—OR^(g), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f),—NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f),naphthyl, —CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is a partially saturated or unsaturated 9-memberedbicyclic ring containing 1 O atom and 1 N atom, wherein the ring issubstituted by 0, 1, 2 or 3 substituents independently selected fromR^(f), R^(g), R^(c), nitro, cyano, —OR^(e), —OR⁹,—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₅alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is a partially saturated or unsaturated 9-memberedbicyclic ring containing 1 S atom and 1 N atom, wherein the ring issubstituted by 0, 1, 2 or 3 substituents independently selected fromR^(f), R^(g), R^(c), nitro, cyano, —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁵ is H.

As stated above, the above embodiments may be used in conjunction withother embodiments listed. The following table is a non-exclusive,non-limiting list some of the combinations of embodiments. Wherein J isNH, Y is N and X is N or CH: Emb. # R¹ R³ R⁴ 1001 A D H 1002 B D H 1003C D H 1004 A E H 1005 B E H 1006 C E H 1007 A F H 1008 B F H 1009 C F H1010 A G H 1011 B G H 1012 C G H 1013 A D I 1014 B D I 1015 C D I 1016 AE I 1017 B E I 1018 C E I 1019 A F I 1020 B F I 1021 C F I 1022 A G I1023 B G I 1024 C G I 1025 A D J 1026 B D J 1027 C D J 1028 A E J 1029 BE J 1030 C E J 1031 A F J 1032 B F J 1033 C F J 1034 A G J 1035 B G J1036 C G J

Wherein J is O, Y is N and X is N or CH: Emb. # R¹ R³ R⁴ 2001 A D H 2002B D H 2003 C D H 2004 A E H 2005 B E H 2006 C E H 2007 A F H 2008 B F H2009 C F H 2010 A G H 2011 B G H 2012 C G H 2013 A D I 2014 B D I 2015 CD I 2016 A E I 2017 B E I 2018 C E I 2019 A F I 2020 B F I 2021 C F I2022 A G I 2023 B G I 2024 C G I 2025 A D J 2026 B D J 2027 C D J 2028 AE J 2029 B E J 2030 C E J 2031 A F J 2032 B F J 2033 C F J 2034 A G J2035 B G J 2036 C G J

Another aspect of the invention relates to a method of treating acute,inflammatory and neuropathic pain, dental pain, general headache,migraine, cluster headache, mixed-vascular and non-vascular syndromes,tension headache, general inflammation, arthritis, rheumatic diseases,osteoarthritis, inflammatory bowel disorders, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, comprising the step of administering a compound according toany of the above embodiments.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound according to any of the above embodiments and apharmaceutically-acceptable diluent or carrier.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments as a medicament.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments in the manufacture of amedicament for the treatment of acute, inflammatory and neuropathicpain, dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, inflammatory eye disorders, inflammatoryor unstable bladder disorders, psoriasis, skin complaints withinflammatory components, chronic inflammatory conditions, inflammatorypain and associated hyperalgesia and allodynia, neuropathic pain andassociated hyperalgesia and allodynia, diabetic neuropathy pain,causalgia, sympathetically maintained pain, deafferentation syndromes,asthma, epithelial tissue damage or dysfunction, herpes simplex,disturbances of visceral motility at respiratory, genitourinary,gastrointestinal or vascular regions, wounds, burns, allergic skinreactions, pruritus, vitiligo, general gastrointestinal disorders,gastric ulceration, duodenal ulcers, diarrhea, gastric lesions inducedby necrotising agents, hair growth, vasomotor or allergic rhinitis,bronchial disorders or bladder disorders.

Another aspect of the invention relates to a method of making a compoundaccording to the above embodiments, comprising the step of:

Another aspect of the invention relates to a method of making a compoundaccording to the above embodiments, comprising the step of: reacting

with R¹M to form

wherein M is B(OH)₂, SnBu₃, ZnCl, BF₃ ⁻, or MgBr.

The compounds of this invention may have in general several asymmetriccenters and are typically depicted in the form of racemic mixtures. Thisinvention is intended to encompass racemic mixtures, partially racemicmixtures and separate enantiomers and diasteromers.

Unless otherwise specified, the following definitions apply to termsfound in the specification and claims:

-   “C_(α-β)alkyl” means an alkyl group comprising a minimum of a and a    maximum of β carbon atoms in a branched, cyclical or linear    relationship or any combination of the three, wherein α and β    represent integers. The alkyl groups described in this section may    also contain one or two double or triple bonds. Examples of    C₁₋₆alkyl include, but are not limited to the following:-   “Benzo group”, alone or in combination, means the divalent radical    C₄H₄═, one representation of which is —CH═CH—CH═CH—, that when    vicinally attached to another ring forms a benzene-like ring—for    example tetrahydronaphthylene, indole and the like.-   The terms “oxo” and “thioxo” represent the groups ═O (as in    carbonyl) and ═S (as in thiocarbonyl), respectively.-   “Halo” or “halogen” means a halogen atoms selected from F, Cl, Br    and I.-   “C_(V-W)haloalkyl” means an alkyl group, as described above, wherein    any number—at least one—of the hydrogen atoms attached to the alkyl    chain are replaced by F, Cl, Br or I.-   “Heterocycle” means a ring comprising at least one carbon atom and    at least one other atom selected from N, O and S. Examples of    heterocycles that may be found in the claims include, but are not    limited to, the following:-   “Available nitrogen atoms” are those nitrogen atoms that are part of    a heterocycle and are joined by two single bonds (e.g. piperidine),    leaving an external bond available for substitution by, for example,    H or CH₃.-   “Pharmaceutically-acceptable salt” means a salt prepared by    conventional means, and are well known by those skilled in the art.    The “pharmacologically acceptable salts” include basic salts of    inorganic and organic acids, including but not limited to    hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,    methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid,    oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid,    succinic acid, maleic acid, salicylic acid, benzoic acid,    phenylacetic acid, mandelic acid and the like. When compounds of the    invention include an acidic function such as a carboxy group, then    suitable pharmaceutically acceptable cation pairs for the carboxy    group are well known to those skilled in the art and include    alkaline, alkaline earth, ammonium, quaternary ammonium cations and    the like. For additional examples of “pharmacologically acceptable    salts,” see infra and Berge et al., J. Pharm. Sci. 66:1 (1977).-   “Saturated, partially saturated or unsaturated” includes    substituents saturated with hydrogens, substituents completely    unsaturated with hydrogens and substituents partially saturated with    hydrogens.-   “Leaving group” generally refers to groups readily displaceable by a    nucleophile, such as an amine, a thiol or an alcohol nucleophile.    Such leaving groups are well known in the art. Examples of such    leaving groups include, but are not limited to,    N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates,    tosylates and the like. Preferred leaving groups are indicated    herein where appropriate.-   “Protecting group” generally refers to groups well known in the art    which are used to prevent selected reactive groups, such as carboxy,    amino, hydroxy, mercapto and the like, from undergoing undesired    reactions, such as nucleophilic, electrophilic, oxidation, reduction    and the like. Preferred protecting groups are indicated herein where    appropriate. Examples of amino protecting groups include, but are    not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and    substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl,    alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples of    aralkyl include, but are not limited to, benzyl, ortho-methylbenzyl,    trityl and benzhydryl, which can be optionally substituted with    halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the    like, and salts, such as phosphonium and ammonium salts. Examples of    aryl groups include phenyl, naphthyl, indanyl, anthracenyl,    9-(9-phenylfluorenyl), phenanthrenyl, durenyl and the like. Examples    of cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals,    preferably have 6-10 carbon atoms, include, but are not limited to,    cyclohexenyl methyl and the like. Suitable acyl, alkoxycarbonyl and    aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl,    iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl,    trifluoroacetyl, trichloro acetyl, phthaloyl and the like. A mixture    of protecting groups can be used to protect the same amino group,    such as a primary amino group can be protected by both an aralkyl    group and an aralkoxycarbonyl group. Amino protecting groups can    also form a heterocyclic ring with the nitrogen to which they are    attached, for example, 1,2-bis(methylene)benzene, phthalimidyl,    succinimidyl, maleimidyl and the like and where these heterocyclic    groups can further include adjoining aryl and cycloalkyl rings. In    addition, the heterocyclic groups can be mono-, di- or    tri-substituted, such as nitrophthalimidyl. Amino groups may also be    protected against undesired reactions, such as oxidation, through    the formation of an addition salt, such as hydrochloride,    toluenesulfonic acid, trifluoroacetic acid and the like. Many of the    amino protecting groups are also suitable for protecting carboxy,    hydroxy and mercapto groups. For example, aralkyl groups. Alkyl    groups are also suitable groups for protecting hydroxy and mercapto    groups, such as tert-butyl.

Silyl protecting groups are silicon atoms optionally substituted by oneor more alkyl, aryl and aralkyl groups. Suitable silyl protecting groupsinclude, but are not limited to, trimethylsilyl, triethylsilyl,triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of an amino groups provide mono- ordi-silylamino groups. Silylation of aminoalcohol compounds can lead to aN,N,O-trisilyl derivative. Removal of the silyl function from a silylether function is readily accomplished by treatment with, for example, ametal hydroxide or ammonium fluoride reagent, either as a discretereaction step or in situ during a reaction with the alcohol group.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride,diphenylmethyl silyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

Protecting groups are removed under conditions which will not affect theremaining portion of the molecule. These methods are well known in theart and include acid hydrolysis, hydrogenolysis and the like. Apreferred method involves removal of a protecting group, such as removalof a benzyloxycarbonyl group by hydrogenolysis utilizing palladium oncarbon in a suitable solvent system such as an alcohol, acetic acid, andthe like or mixtures thereof. A t-butoxycarbonyl protecting group can beremoved utilizing an inorganic or organic acid, such as HCl ortrifluoroacetic acid, in a suitable solvent system, such as dioxane ormethylene chloride. The resulting amino salt can readily be neutralizedto yield the free amine. Carboxy protecting group, such as methyl,ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can beremoved under hydrolysis and hydrogenolysis conditions well known tothose skilled in the art.

It should be noted that compounds of the invention may contain groupsthat may exist in tautomeric forms, such as cyclic and acyclic amidineand guanidine groups, heteroatom substituted heteroaryl groups (Y′═O, S,NR), and the like, which are illustrated in the following examples:

and though one form is named, described, displayed and/or claimedherein, all the tautomeric forms are intended to be inherently includedin such name, description, display and/or claim.

Prodrugs of the compounds of this invention are also contemplated bythis invention. A prodrug is an active or inactive compound that ismodified chemically through in vivo physiological action, such ashydrolysis, metabolism and the like, into a compound of this inventionfollowing administration of the prodrug to a patient. The suitabilityand techniques involved in making and using prodrugs are well known bythose skilled in the art. For a general discussion of prodrugs involvingesters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) andBundgaard Design of Prodrugs, Elsevier (1985). Examples of a maskedcarboxylate anion include a variety of esters, such as alkyl (forexample, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl(for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (forexample, pivaloyloxymethyl). Amines have been masked asarylcarbonyloxymethyl substituted derivatives which are cleaved byesterases in vivo releasing the free drug and formaldehyde (Bungaard J.Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, suchas imidazole, imide, indole and the like, have been masked withN-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloanand Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acidprodrugs, their preparation and use.

The specification and claims contain listing of species using thelanguage “selected from . . . and . . . ” and “is . . . or . . . ”(sometimes referred to as Markush groups). When this language is used inthis application, unless otherwise stated it is meant to include thegroup as a whole, or any single members thereof, or any subgroupsthereof. The use of this language is merely for shorthand purposes andis not meant in any way to limit the removal of individual elements orsubgroups as needed.

Experimental

Unless otherwise noted, all materials were obtained from commercialsuppliers and used without further purification. All parts are by weightand temperatures are in degrees centigrade unless otherwise indicated.All microwave assisted reactions were conducted with a SmithSynthesizer™ from Personal Chemistry, Uppsala, Sweden, or with anExplorer® Automated Synthesis workstation from CEM Corp., Matthews, N.C.All compounds showed NMR spectra consistent with their assignedstructures. Melting points were determined on a Buchi apparatus and areuncorrected. Mass spectral data was determined by electrosprayionization technique. All examples were purified to>90% purity asdetermined by high-performance liquid chromatography. Unless otherwisestated, reactions were run at room temperature.

The following abbreviations are used:

-   DMSO—dimethyl sulfoxide-   DMF—N,N-dimethylformamide-   THF—tetrahydrofuran-   Et₂O—diethyl ether-   EtOAc—ethyl acetate-   MeOH—methyl alcohol-   EtOH—ethyl alcohol-   MeCN—acetonitrile-   MeI—iodomethane-   NMP—1-methyl-2-pyrrolidinone-   DCM—dichloromethane-   TFA—trifluoroacetic acid-   sat.—saturated-   h—hour-   min—minutes-   mL milliliters-   g grams-   mg milligrams    Generic Schemes for the Preparation of Pyridine Core (I):    Generic Schemes for the Preparation of Pyrimidine Core (II):

EXAMPLE 1

6-[4-(tert-Butyl)phenyl]-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(4-methylpiperazin-1-yl)pyrimidin-4-amine

(a) 6-[4-(tert-Butyl)phenyl]-2,4-dichloropyrimidine.

To a 250-mL, round-bottomed flask containing 2,4,6-trichloropyrimidine(26 g, 0.14 mol, Aldrich) in CH₃CN (100 mL), was added4-tert-butylphenylboronic acid (7.2 g, 40 mmol, Aldrich), Pd(PPh₃)₄ (1.4g, 1.2 mmol, Aldrich) and 10% aq. Na₂CO₃ (60 mL), and the mixture washeated at 90° C. with stirring under N₂ for 18 h. The reaction mixturewas left to reach room temperature and was diluted with EtOAc (80 mL),CH₃CN (50 mL), and water (50 mL). The solid precipitate was filtered anddissolved in CH₂Cl₂ (140 mL). The solution was washed with sat. NaCl (60mL), dried over Na₂SO₄, filtered, and concentrated in vacuo.Purification of the residue by silica gel column chromatography (6:1hexane/EtOAc) provided the title product. MS (ESI, pos. ion) m/z: 281(M+1).

(b) 2H,3H-Benzo[e]1,4-dioxan-6-yl{6-[4-(tert-butyl)phenyl]-2-chloropyrimidin-4-yl}amine.

To a 250-mL, round-bottomed flask containing a solution of6-[4-(tert-butyl)phenyl]-2,4-dichloropyrimidine from step (a) above (3.0g, 11 mmol) in a 1:1 EtOH/1,4-dioxane mixture (100 mL) was added1,4-benzodioxane-6-amine (1.3 g, 8.6 mmol, Aldrich). The reactionmixture was stirred at 25° C. for 18 h, and the solvent was removed invacuo. Purification of the residue by silica gel column chromatography(6:1 hexane/EtOAc) provided the title product as an off-white solid. MS(ESI, pos. ion) m/z: 396 (M+1).

(c)6-[4-(tert-Butyl)phenyl]-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(4-methylpiperazin-1-yl)pyrimidin-4-amine.

To a 50-mL, round-bottomed flask containing2H,3H-benzo[e]1,4-dioxan-6-yl{6-[4-(tert-butyl)phenyl]-2-chloropyrimidin-4-yl}amine from step (b)above (0.13 g, 0.33 mmol) in EtOH (4 mL) was added 4-methylpiperazine(58 μL, 0.53 mmol, Aldrich). The reaction mixture was refluxed for 6 h,and the solvent was removed in vacuo. Purification of the residue bysilica gel column chromatography (3:3:1 hexane/EtOAc/MeOH) provided thetitle product as an oil. MS (ESI, pos. ion) m/z: 460 (M+1). TABLE 1 Thefollowing examples were prepared from 2H,3H-benzo[e]1,4-dioxan-6-yl{6-[4-(tert-butyl)phenyl]-2-chloropyrimidin-4-yl}amine(Example 1(b)) and commercially available amines according to theprocedure described for the preparation of Example 1(c), or with slightmodifications to that procedure. Melting Point Mass Spec. ExampleStructure (° C.) (ESI) m/z 2

oil 421 (M + 1) 3

oil 474 (M + 1) 4

amorphous solid 490 (M + 1) 5

amorphous solid 448 (M + 1)

EXAMPLE 6

6-(4-tert-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methoxypyrimidin-4-amine

(a) 4-[4-(tert-Butyl)phenyl]-6-chloro-2-(methylthio)pyrimidine.

2-Methylthio-4,6-dichloropyrimidine (12 g, 62 mmol, Aldrich) reactedwith 4-tert-butylphenylboronic acid (11 g, 62 mmol, Aldrich) under theconditions of Example 1(a) to give the title compound. MS (ESI, pos.ion) m/z: 293 (M+1).

(b)6-(4-tert-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(methylthio)pyrimidin-4-amine.

To a 250-mL, round-bottomed flask containing a solution of4-[4-(tert-butyl)phenyl]-6-chloro-2-(methylthio)pyrimidine from step (a)above (13 g, 43 mmol) in 2:1 EtOH/CH₂Cl₂ mixture (150 mL) was added1,4-benzodioxane-6-amine (6.5 g, 43 mmol, Aldrich). The reaction mixturewas refluxed for 18 h, and the solvent was removed in vacuo.Purification by silica gel column chromatography (56:1 hexane/EtOAc)provided the title product. MS (ESI, pos. ion) m/z: 408 (M+1).

(c)6-(4-tert-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(methylsulfonyl)pyrimidin-4-amine.

To a 50-mL, round-bottomed flask containing a solution of6-(4-tert-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(methylthio)pyrimidin-4-aminefrom step (b) above (0.41 g, 1.0 mmol) in CH₂Cl₂ (10 mL) was addedm-CPBA (0.38 g, 2.2 mmol, Aldrich). The reaction mixture was stirred atroom temperature for 0.5 h, and the solvent was removed in vacuo. Theresidue was dried in vacuo to provide the title product. MS (ESI, pos.ion) m/z: 439 (M+1).

(d)6-(4-tert-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methoxypyrimidin-4-amine.

To a 50-mL, round-bottomed flask containing a solution of6-(4-tert-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(methylsulfonyl)pyrimidin-4-aminefrom step (c) above (0.20 g, 0.46 mmol) in MeOH (10 mL) was added NaOMe(76 mg, 1.4 mmol, Aldrich). The reaction mixture was refluxed for 2 h,and the solvent was removed in vacuo. Purification of the residue bysilica gel column chromatography (4:1 hexane/EtOAc) provided the titleproduct as a yellow solid. MS (ESI, pos. ion) m/z: 392 (M+1).

EXAMPLE 7

N-{4-[2-(2-Morpholin-4-yl-ethyl)-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide

(a) 2,4-Dichloro-6-(4-trifluoromethyl-phenyl)-pyrimidine.

A mixture of 2,4,6-trichloropyrimidine (502 mg, 2.74 mmol, Aldrich),4-tri-fluoromethyl-phenylboronic acid (510 mg, 2.69 mmol, Aldrich),Pd(OAc)₂ (31 mg, 0.14 mmol), PPh₃ (71 mg, 0.27 mmol, Aldrich) and 2NNa₂CO₃ (3.1 mL) in 1,2-dimethoxyethane (9.0 mL) was heated at 120° C. ina microwave synthesizer for 20 min. The reaction mixture was cooled toroom temperature, diluted with saturated aqueous solution of NaHCO₃ (10mL) and extracted with EtOAc (2×50 mL). The combined EtOAc extracts weredried over Na₂SO₄, filtered, and concentrated in vacuo. Purification ofthe residue by silica gel column chromatography (gradient 3-12%EtOAc/hexane) gave the title compound as an off-white solid. MS (ESI,pos. ion.) m/z: 294 (M+1).

(b) Acetic acid 2-acetylamino-benzothiazol-4-yl ester.

To a suspension of 2-amino-4-hydroxybenzothiazole (8.3 g, 50 mmol,Fluorochem Ltd.) in toluene (100 mL) was added acetic anhydride (47 mL,500 mmol), and the mixture was heated at 110° C. for 16 h. The reactionmixture was cooled to room temperature and evaporated in vacuo to givethe title compound as a tan solid. MS (ESI, pos. ion.) m/z: 251 (M+1).

(c) N-(4-Hydroxy-benzothiazol-2-yl)-acetamide.

To a suspension of acetic acid 2-acetylamino-benzothiazol-4-yl esterfrom step (b) above (9.7 g, 39 mmol) in MeOH (200 mL) was addedpotassium carbonate (11 g, 78 mmol). The reaction mixture was stirred at25° C. for 6 h and then evaporated under vacuo. The residue wasacidified with 10% HCl to pH 5 and extracted with EtOAc (3×). Thecombined EtOAc extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo to give the title compound as a tansolid. MS (ESI, pos. ion.) m/z: 209 (M+1).

(d)N-{4-[2-Chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.

A mixture of 2,4-dichloro-6-(4-trifluoromethyl-phenyl)-pyrimidine fromstep (a) above (700 mg, 2.38 mmol),N-(4-hydroxy-benzothiazol-2-yl)-acetamide from step (c) above (474 mg,2.27 mmol) and K₂CO₃ (394 mg, 2.86 mmol) in DMF (5 mL) and THF (3 mL)was heated at 50° C. for 2 h. The reaction mixture was cooled to roomtemperature, diluted with EtOAc (100 mL), and washed with 1N NaOH (10mL). The EtOAc layer was separated, dried over Na₂SO₄, filtered, andconcentrated in vacuo. Purification of the residue by silica gel columnchromatography (gradient 30-75% EtOAc/hexane) provided the titlecompound as an off-white solid. MS (ESI, pos. ion.) m/z: 487 (M+Na).

(e)N-{4-[6-(4-Trifluoromethyl-phenyl)-2-vinyl-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.

A mixture ofN-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamidefrom step (d) above (540 mg, 1.16 mmol), tributyl(vinyl)tin (551 mg,1.74 mmol, Aldrich) and Pd(PPh₃)₄ (108 mg, 0.09 mmol, Aldrich) intoluene (4 mL) and dioxane (4 mL) was heated at 140° C. in a microwavesynthesizer for 25 min. The mixture was cooled to room temperature,diluted with EtOAc (60 mL) and washed with sat. aqueous solution ofNaHCO₃ (5 mL). The EtOAc layer was separated, dried over Na₂SO₄,filtered, and concentrated in vacuo. Purification of the residue bysilica gel column chromatography (gradient 30-80% EtOAc/hexane) providedthe title compound as a light-yellow solid. MS (ESI, pos. ion.) m/z: 457(M+1).

(f)N-{4-[2-(2-Morpholin-4-yl-ethyl)-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.

A mixture ofN-{4-[6-(4-trifluoromethyl-phenyl)-2-vinyl-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamidefrom step (e) above (60 mg, 0.13 mmol), morpholine (22.6 mg, 0.26 mmol,Aldrich) and acetic acid (14 mg, 0.23 mmol) in ethanol (1 mL) was heatedat 120° C. in a microwave synthesizer for 30 min. The reaction mixturewas cooled to room temperature and the volatiles were evaporated invacuo. The residue was treated with sat. aqueous solution of NaHCO₃ (5mL) and extracted with EtOAc (2×30 mL). The combined EtOAc extracts weredried over Na₂SO₄, filtered, and concentrated in vacuo. Purification ofthe residue by silica gel column chromatography (gradient 5-15%MeOH/EtOAc) provided the title compound as a brown amorphous. solid. MS(ESI, pos. ion.) m/z: 544 (M+1). TABLE 2 The following examples wereprepared from of N-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide(93 mg, 0.2 mmol, Example 7(d)) and commercially availabletributylstanyl reagents according to the procedure described for thepreparation of Example 7(e), or with slight modifications to thatprocedure. Melting Point Mass Spec. Example Structure (° C.) (ESI) m/z 8

amorphous solid 508 (M + 1) 9

268-270 508 (M + 1) 10

amorphous solid 510 (M + 1) 11

amorphous solid 509 (M + 1)

EXAMPLE 12

N-(4-(2-(2-(tert-Butylamino)ethyl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-+trifluoroacetic acid salt

N-{4-[6-(4-Trifluoromethyl-phenyl)-2-vinyl-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide(60 mg, 0.13 mmol, Example 7(e)) reacted with tert-butylamine (100 mg,1.37 mmol, Aldrich) under the conditions of Example 7(f). The crudeproduct was purified by preparative HPLC [gradient 20-80% MeCN (0.1%TFA) H₂O (0.1% TFA)] to give the title compound as a pale-yellow solid.MS (ESI, pos. ion.) m/z: 530 (M+1).

EXAMPLE 13

4-(2-(2-(tert-Butylamino)ethyl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-amine,trifluoroacetic acid salt

This compound was formed as a side product of the reaction described inExample 12 and was isolated as a pale yellow amorphous solid afterpurification by preparative HPLC [gradient 20-80% MeCN (0.1% TFA)/H₂O(0.1% TFA)]. MS (ESI, pos. ion.) m/z: 488 (M+1). TABLE 3 The followingexamples were prepared by reacting N-{4-[6-(4-trifluoromethyl-phenyl)-2-vinyl-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide(Example 7(e)) with commercially available amines according to theprocedures described in Example 12 and Example 13 or with slightmodifications to those procedures. Melting Point Mass Spec. ExampleStructure (° C.) (ESI) m/z 14

amorphous solid 556 (M + 1) 15

amorphous solid 514 (M + 1) 16

amorphous solid 500 (M + 1) 17

amorphous solid 542 (M + 1) 18

amorphous solid 570 (M + 1) 19

amorphous solid 560 (M + 1) 20

amorphous solid 560 (M + 1) 21

amorphous solid 596 (M + 1) 22

amorphous solid 528 (M + 1)

EXAMPLE 23

N-{4-[2-Pyridin-4-yl-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide

A mixture ofN-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide(137 mg, 0.29 mmol, Example 7(d)), 4-pyridinyl boronic acid (40 mg, 0.32mmol, Aldrich), Pd(PPh₃)₄ (24 mg, 0.02 mmol, Aldrich) and 2N Na₂CO₃ (0.5mL) in 1,2-dimethoxyethane (1.5 mL) was heated at 125° C. in a microwavesynthesizer for 20 min. The reaction mixture was cooled to roomtemperature, diluted with sat. aqueous solution of NaHCO₃ (5 mL) andextracted with EtOAc (2×30 mL). The combined EtOAc extracts were driedover Na₂SO₄, filtered, and concentrated in vacuo. Purification of theresidue by silica gel column chromatography (gradient 50-90%EtOAc/hexane) gave the title compound as a light-yellow amorphous solid.MS (ESI, pos. ion.) m/z: 508 (M+1).

EXAMPLE 24

4-[2-Pyridin-4-yl-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine

This compound was formed as a side product of the reaction described inExample 23 and was isolated as a pale-yellow amorphous solid afterpurification by silica gel column chromatography (gradient 50-90%EtOAc/hexane). MS (ESI, pos. ion.) m/z: 466 (M+1).

EXAMPLE 25

N-{4-[2-Cyano-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide

A mixture ofN-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide(237 mg, 0.519 mmol, Example 7(d)), zinc cyanide (32 mg, 0.27 mmol) andPd(PPh₃)₄ (47 mg, 0.04 mmol, Aldrich) in DMF (1.0 mL) and1,2-dimethoxyethane (1.0 mL) was heated at 130° C. in a microwavesynthesizer for 20 min. The reaction mixture was cooled to roomtemperature, diluted with saturated aqueous solution of NaHCO₃ (10 mL)and extracted with EtOAc (3×30 mL). The combined EtOAc extracts weredried over Na₂SO₄, filtered, and concentrated in vacuo. Purification ofthe residue by silica gel column chromatography (gradient 35-80%EtOAc/hexane) gave the title compound as a light-yellow solid. MS (ESI,pos. ion.) m/z: 456 (M+1).

EXAMPLE 26

4-(2-(Aminomethyl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]-thiazol-2-amine,trifluoroacetic acid salt

To a solution ofN-{4-[2-cyano-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide(128 mg, 0.28 mmol, Example 25) in anhydrous DCM (3 mL) was addeddiisobutylaluminum hydride (0.98 mL of 1M solution in DCM, 0.98 mmol,Aldrich) dropwise with stirring at −78° C. The reaction mixture waswarmed to 0° C. for 1 h, quenched with saturated aqueous solution ofpotassium sodium tartrate and extracted with DCM (×2). The combined DCMextracts were dried over Na₂SO₄, filtered, and concentrated in vacuo.Purification of the residue by preparative HPLC [gradient 20-80% MeCN(0.1% TFA)/H₂O (0.1% TFA)] gave the title compound as a pale-yellowsolid. MS (ESI, pos. ion.) m/z: 418 (M+1).

EXAMPLE 27

N-(4-(2-(1,2,3,6-Tetrahydropyridin-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide

A mixture ofN-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide(300 mg, 0.645 mmol, Example 7(d)), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(216 mg, 0.70 mmol, Aldrich), Pd(OAc)₂ (7.2 mg, 0.03 mmol, Aldrich),PPh₃ (17 mg, 0.065 mmol) and 2N aqueous Na₂CO₃ (0.65 mL) in1,2-dimethoxyethane (3.0 mL) was heated at 120° C. in a microwavesynthesizer for 25 min. The reaction mixture was cooled to roomtemperature, diluted with saturated aqueous solution of NaHCO₃ (10 mL)and extracted with EtOAc (2×50) mL. The combined EtOAc extracts weredried over Na₂SO₄, filtered, and concentrated in vacuo. The yellow solidresidue was dissolved in DCM (4 mL) and treated with trifluoroaceticacid (1 mL). The mixture was stirred at room temperature for 1.5 h andthe volatiles were evaporated in vacuo. The residue was partitionedbetween 1N HCl (5 mL) and Et₂O (5 mL). The aqueous layer was separated,basified with 2N NaOH, and extracted with EtOAc (3×15 mL). The combinedEtOAc extracts were dried over Na₂SO₄, filtered, and concentrated invacuo. Purification of the residue by silica gel column chromatography(gradient 1-25% (2N NH₃ in MeOH)/EtOAc) afforded the title compound asan off-white solid. MS (ESI, pos. ion.) m/z: 512 (M+1).

EXAMPLE 28

N-(4-(2-(1-Isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(4-(trifluoromethyl)-phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide

To a mixture ofN-(4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide(109 mg, 0.195 mmol, Example 27), acetone (1 mL), 1,2-dichloroethane (6mL) and DMF (0.5 mL) was added AcOH (one drop), and the mixture washeated at 50° C. with stirring for 10 min. The reaction mixture was leftto reach room temperature, sodium triacetoxyborohydride (127 mg, 0.6mmol, Aldrich) was added, and the stirring was continued for 2 h at roomtemperature. After the addition of acetone (1 mL) and sodiumtriacetoxyborohydride (127 mg, 0.6 mmol), the reaction mixture wasstirred at room temperature for 1 h and evaporated under reducedpressure. The yellow residue was treated with 1N NaOH (5 mL) andextracted with EtOAc (2×20 mL). The combined EtOAc extracts were driedover Na₂SO₄, filtered, and concentrated in vacuo. Purification of theresidue by silica gel column chromatography (gradient 0.5-5% (2M NH₃ inMeOH) in EtOAc) afforded the title compound as a pale-yellow amorphoussolid. MS (ESI, pos. ion.) m/z: 554 (M+1).

EXAMPLE 29

N-(4-(2-(3-(Pyrrolidin-1-ylmethyl)pyridin-4-yl)-6-(4-(trifluoromethyl)phenyl)-pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide,trifluoroacetic acid salt

(a)N-(4-(2-(3-Formylpyridin-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide.

The reaction ofN-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzo[d]thiazol-2-yl}-acetamide(279 mg, 0.6 mmol, Example 7(d)) and4-tributylstannylpyridine-3-carboxaldehyde (295 mg, 0.8 mmol, Frontier)under the conditions of Example 7(e) provided the title compound as abrown amorphous solid. MS (ESI, pos. ion) m/z: 536 (M+1).

(b)N-(4-(2-(3-(Pyrrolidin-1-ylmethyl)pyridin-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide,trifluoroacetic acid salt.

A mixture ofN-(4-(2-(3-formylpyridin-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamidefrom step (a) above (54 mg, 0.1 mmol) and pyrrolidine (14 mg, 0.2 mmol,Aldrich) in chloroform (5 mL) was stirred at room temperature for 10min. To the reaction mixture was added NaBH(OAc)₃ (63 mg, 0.3 mmol,Aldrich) and AcOH (1 drop), and the stirring was continued for 1 h. Themixture was washed with sat. aqueous solution of NaHCO₃ s (10 mL), driedover Na₂SO₄, and filtered. The filtrate was evaporated in vacuo and theresidue was purified by preparative HPLC [gradient 20-80% MeCN (0.1%TFA)/H₂O (0.1% TFA)] to give the title compound as salt with TFA. MS(ESI, pos. ion) m/z: 591 (M+1)

EXAMPLE 30

N-(4-(2-(3-(Hydroxymethyl)pyridin-4-yl)-6-(4-(trifluoromethyl)phenyl)-pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide

A mixture ofN-(4-(2-(3-formylpyridin-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide(54 mg, 0.1 mmol, Example 29(a)), NaBH(OAc)₃ (63 mg, 0.3 mmol, Aldrich)in chloroform (5 mL) was stirred at room temperature for 16 h. Thereaction mixture was washed with sat. aqueous solution of NaHCO₃ (10mL), dried over Na₂SO₄, and filtered. The filtrate was evaporated invacuo and the residue was purified by preparative HPLC [gradient 20-80%MeCN (0.1% TFA)/H₂O (0.1% TFA)] to give the title compound as salt withTFA. MS (ESI, pos. ion) m/z: 538 (M+1).

EXAMPLE 31

N-(4-(2-(1-Isopropylpiperidin-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide

To a mixture ofN-(4-(2-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide(100 mg, 0.18 mmol, Example 28), HCO₂N44 (227 mg, 3.6 mmol, Aldrich) inbutanol (2 mL) was added palladium hydroxide (8.3 mg, 0.016 mmol, 20 wt.% Pd (dry basis) on carbon, Aldrich), and the mixture was heated to 120°C. for 16 h with stirring under nitrogen atmosphere. After cooling toroom temperature, the reaction mixture was filtered through Celite® pad.The filter cake was washed with MeOH and the combined filtrates wereevaporated under reduced pressure. The residue was purified by silicagel column chromatography (7% MeOH/DCM) to provide the title compound asan amorphous solid. MS (ESI, pos. ion) m/z: 556 (M+1).

EXAMPLE 32

tert-Butyl4-(4-(2-acetamidobenzo[d]thiazol-4-yloxy)-6-(4-(trifluoromethyl)-phenyl)pyrimidin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate

A mixture ofN-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzo[d]thiazol-2-yl}-acetamide(279 mg, 0.6 mmol, Example 7(d)), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (309 mg, 1.0 mmol, ChemShop), PdCl₂(PPh₃)₂ (42 mg, 0.06mmol, Aldrich), Na₂CO₃.H₂O (74 mg, 0.6 mmol), dimethoxyethane (0.7 mL),H₂O (0.3 mL) and EtOH (0.2 mL) was heated in a microwave synthesizer at120° C. with stirring for 10 min. The reaction mixture was diluted withwater (15 mL) and extracted with EtOAc (2×30 mL). The combined organicphases were washed with brine (20 mL), dried over Na₂SO₄ and filtered.The filtrate was evaporated in vacuo and the residue was purified bysilica gel column chromatography (30% EtOAc/hexane) to give the titlecompound. MS (ESI, pos. ion) m/z: 612 (M+1).

EXAMPLE 33

N-(4-(2-(1-Isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(4-(trifluoromethyl)-phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide

The reaction ofN-(4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-6-(4-(trifluoromethyl)-phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide(92 mg, 0.15 mmol, Example 27) and isobutylaldehyde (22 mg, 0.3 mmol,Aldrich) under the conditions of Example 28 gave the title compound as awhite amorphous solid. MS (ESI, pos. ion) m/z: 568 (M+1).

EXAMPLE 34

tert-Butyl4-(4-(2-acetamidobenzo[d]thiazol-4-yloxy)-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)piperazine-1-carboxylate

A mixture ofN-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide(186 mg, 0.4 mmol, Example 7(d)) and tert-butyl 1-piperazine-carboxylate(149 mg, 0.8 mmol, Aldrich) in ethanol (1 mL) was heated in a microwavesynthesizer at 125° C. for 40 min. The reaction mixture was evaporatedunder reduced pressure and the residue was treated with sat. aqueoussolution of NaHCO₃ (10 mL), and extracted with EtOAc (2×30 mL). Thecombined EtOAc extracts were washed with brine, dried over Na₂SO₄ andfiltered. The filtrate was evaporated in vacuo and the residue waspurified by silica gel column chromatography (20% EtOAc/hexane) to givethe title compound as a solid. MS (ESI, pos. ion) m/z: 615 (M+1). M.p.:211° C.

EXAMPLE 35

N-(4-(2-(Piperazin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide,trifluoroacetic acid salt

To a solution of tert-butyl4-(4-(2-acetamidobenzo[d]thiazol-4-yloxy)-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)piperazine-1-carboxylate(140 mg, 0.23 mmol, Example 34) in DCM (2 mL) was added trifluoroaceticacid (2 mL) and the mixture was stirred at room temperature for 1.5 h.The reaction mixture was evaporated under reduced pressure and theresidue was purified by preparative HPLC [gradient 20-80% MeCN (0.1%TFA)/H₂O (0.1% TFA)] to give the title compound as salt with TFA. MS(ESI, pos. ion.) m/z: 515 (M+1).

EXAMPLE 36

N-(4-(2-(4-Isobutylpiperazin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide,trifluoroacetic acid salt

To a solution ofN-(4-(2-(piperazin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide,trifluoroacetic acid salt (63 mg, 0.1 mmol, Example 35) andisobutylaldehyde (15 mg, 0.2 mmol, Aldrich) in 1,2-dichloroethane (3 mL)and DMF (0.5 mL) was added sodium triacetoxyborohydride (85 mg, 0.4mmol, Aldrich) and the mixture was stirred at room temperature for 1 h.The reaction mixture was evaporated under reduced pressure and theresidue was treated with sat. aqueous solution of NaHCO₃ (5 mL), andextracted with EtOAc (2×20 mL). The combined EtOAc extracts were washedwith brine, dried over Na₂SO₄ and filtered. The filtrate was evaporatedin vacuo and the residue was purified by preparative HPLC [gradient20-80% MeCN (0.1% TFA)/H₂O (0.1% TFA)] to give the title compound assalt with TFA. MS (ESI, pos. ion.) m/z: 571 (M+1). TABLE 4 The followingexamples were prepared from N-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzo[d]thiazol-2-yl}acetamide(Example 7(d)) and commercially available amines according to theprocedure described for the preparation of Example 34, or with slightmodifications to that procedure. Melting Point Mass Spec. ExampleStructure (° C.) (ESI) m/z 37

amorphous solid 530 (M + 1) 38

amorphous solid 568 (M + 1) 39

198 530 (M + 1) 40

amorphous solid 573 (M + 1) 41

amorphous solid 559 (M + 1) 42

277-278 558 (M + 1) 43

amorphous solid 599 (M + 1) 44

amorphous solid 637 (M + 1) 45

amorphous solid 568 (M + 1) 46

amorphous solid 540 (M + 1) 47

amorphous solid 531 (M + 1) 48

amorphous solid 504 (M + 1) 49

amorphous solid 571 (M + 1) 50

amorphous solid 551 (M + 1) 51

amorphous solid 551 (M + 1) 52

amorphous solid 537 (M + 1) 53

240 537 (M + 1) 54

amorphous solid 562 (M + 1) 55

amorphous solid 571 (M + 1) 56

amorphous solid 556 (M + 1) 57

amorphous solid 556 (M + 1) 58

amorphous solid 518 (M + 1) 59

amorphous solid 540 (M + 1) 60

amorphous solid 647 (M + 1) 61

amorphous solid 517 (M + 1) 62

amorphous solid 587 (M + 1) 63

amorphous solid 530 (M + 1) 64

amorphous solid 514 (M + 1) 65

amorphous solid 552 (M + 1) 66

amorphous solid 585 (M + 1) 67

amorphous solid 529 (M + 1) 68

amorphous solid 645 (M + 1) 69

amorphous solid 601 (M + 1) 70

128 643 (M + 1) 71

132 629 (M + 1)

EXAMPLE 72

N-(4-(2-(2-(4,4-Difluoropiperidin-1-yl)ethylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide,trifluoroacetic acid salt

(a) 2-(4,4-Difluoropiperidin-1-yl)ethanamine.

A solution of (4,4-difluoropiperidin-yl)-acetonitrile (0.48 g, 3 mmol,Matrix) in THF (5 mL) was added dropwise to a 1M solution of LiAlH₄ inTHF (5 ml, Aldrich) with stirring at room temperature. The reactionmixture was stirred at room temperature for 16 h and then treated withwater (1 mL) and 20% aqueous solution of KOH (10 mL). The mixture wasfiltered and the filtrate was extracted with EtOAc (3×60 mL). Thecombined EtOAc extracts were washed with brine, dried over Na₂SO₄ andfiltered. The filtrate was evaporated in vacuo and the residue waspurified by silica gel chromatography (MeOH) to give the title compoundas an yellow oil. MS (ESI, pos. ion) m/z: 165 (M+1).

(b)N-(4-(2-(2-(4,4-Difluoropiperidin-1-yl)ethylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide,trifluoroacetic acid salt.

N-{4-[2-Chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide(186 mg, 0.4 mmol, Example 7(d)) reacted with2-(4,4-difluoropiperidin-1-yl)ethanamine from step (a) above (131 mg,0.8 mmol) under the conditions of Example 34. The crude product waspurified by preparative HPLC [gradient 20-80% MeCN (0.1% TFA)/H₂O (0.1%TFA)] to give the title compound as a salt with TFA. White amorphoussolid. MS (ESI, pos. ion.) m/z: 593 (M+1).

EXAMPLE 73

4-(2-(2-(4,4-Difluoropiperidin-1-yl)ethylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-amine,trifluoroacetic acid salt

This compound was formed as a side product of the reaction described inExample 72(b) and was isolated as salt with TFA after purification bypreparative HPLC [gradient 20-80% MeCN (0.1% TFA)/H₂O (0.1% TFA)]. MS(ESI, pos. ion.) m/z: 551 (M+1).

EXAMPLE 74

4-(2-(1-(Pyridin-2-yl)ethylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-amine

This compound was formed as a side product of the reaction described inExample 51 and was isolated as a white amorphous solid afterpurification by silica gel column chromatography MS (ESI, pos. ion.)m/z: 509 (M+1). TABLE 5 The following examples were was formed as sideproducts of the reaction ofN-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide (186 mg, 0.4 mmol, Example 7(d)) andcommercially available amines according to the procedure described forthe preparation of Example 34, or with slight modifications to thatprocedure. Melting Example Point Mass Spec. # Structure (° C.) (ESI) m/z75

amorphous solid 520 (M + 1) 76

amorphous solid 529 (M + 1) 77

amorphous solid 514 (M + 1) 78

amorphous solid 476 (M + 1) 79

amorphous solid 545 (M + 1) 80

amorphous solid 475 (M + 1)

EXAMPLE 81

4-(2-(2-Methyl-2-(piperidin-1-yl)propylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-amine

To a mixture of4-(2-(2-amino-2-methylpropylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-amine(47 mg, 1.0 mmol, Example 80) and 50% aqueous solution of glutaricdialdehyde (40 mg, 0.2 mmol, Aldrich) in 1,2-dichloroethane (2 mL) wasadded sodium triacetoxyborohydride (212 mg, 1.0 mmol, Aldrich) and themixture was stirred at room temperature for 1 h. The reaction mixturewas evaporated under reduced pressure and the residue was treated withsat. aqueous solution of NaHCO₃ (5 mL), and extracted with EtOAc (2×20mL). The combined EtOAc extracts were washed with brine, dried overNa₂SO₄ and filtered. The filtrate was evaporated in vacuo and theresidue was purified by silica gel column chromatography (10% MeOH/DCM)to afford the title compound as a white amorphous solid. MS (ESI, pos.ion.) m/z: 543 (M+1).

EXAMPLE 82

4-(2-(1-(4-Fluorophenyl)ethylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-amine

(a)4-(2-Chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-amine.

The reaction of 2,4-dichloro-6-(4-trifluoromethyl-phenyl)-pyrimidine(480 mg, 1.64 mmol, Example 7(a)) with 2-aminobenzo[d]thiazol-4-ol (272mg, 1.64 mmol, Astatech) under the conditions of Example 7(d) providedthe title compound as a solid. M.p.: 231° C. MS (ESI, pos. ion) m/z: 423(M+1).

(b)4-(2-(1-(4-Fluorophenyl)ethylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-amine

The reaction of4-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-aminefrom step (a) above (106 mg, 0.5 mmol) with4-fluoro-alpha-methylbenzylamine (70 mg, 0.5 mmol, Aldrich) under theconditions of Example 34 provided the title compound as an amorphoussolid. MS (ESI, pos. ion) m/z: 526 (M+1).

EXAMPLE 83

4-(2-(1-(3-Fluorophenyl)ethylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-amine

The reaction of4-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-aminefrom step (a) above (106 mg, 0.25 mmol) with(R,S)-1-(3-fluorophenyl)ethylamine (70 mg, 0.5 mmol, Indofine) under theconditions of Example 34 provided the title compound as an amorphoussolid. MS (ESI, pos. ion) m/z: 526 (M+1). TABLE 6 The following exampleswere prepared by cleavage of the Boc- protective group of the compoundslisted as Examples 68-71 according to the procedure described for thepreparation of Example 35, or with slight modifications to thatprocedure. Melting Point Mass Spec. Example Structure (° C.) (ESI) m/z84

amorphous solid 545 (M + 1) 85

amorphous solid 543 (M + 1) 86

amorphous solid 543 (M + 1) 87

amorphous solid 529 (M + 1)

TABLE 7 The following examples were prepared from the compounds listedas Examples 35, 67, 84-87 and commercially available aldehydes orketones according to the procedure described for the preparation ofExample 36, or with slight modifications to that procedure. MeltingPoint Mass Spec. Example Structure (° C.) (ESI) m/z 88

amorphous solid 557 (M + 1) 89

amorphous solid 585 (M + 1) 90

amorphous solid 571 (M + 1) 91

amorphous solid 599 (M + 1) 92

amorphous solid 587 (M + 1) 93

amorphous solid 601 (M + 1) 94

amorphous solid 597 (M + 1) 95

amorphous solid 597 (M + 1) 96

amorphous solid 599 (M + 1) 97

amorphous solid 585 (M + 1)

EXAMPLE 98

N-(4-(2-(Hydroxymethyl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)-benzo[d]thiazol-2-yl)acetamide

The reaction ofN-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzo[d]thiazol-2-yl}-acetamide(233 mg, 0.5 mmol, Example 7(d)) and tributylstannyl-methanol (322 mg,1.0 mmol, prepared according to the procedure described in SyntheticCommunication, 1994, 24, 1117-1120) under the conditions of Example 7(e)gave the title compound as a white amorphous solid. MS (ESI, pos. ion)m/z: 461 (M+1).

EXAMPLE 99

N-(4-(2-(Piperidin-1-ylmethyl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide,trifluoroacetic acid salt

(a)N-(4-(2-Formyl-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide

To a solution ofN-(4-(2-(hydroxymethyl)-6-(4-(trifluoromethyl)phenyl)-pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide(80 mg, 0.174 mmol, Example 98) in DCM (2 mL) was added oxalyl chloride(0.35 mL, 2M solution in DCM, 0.7 mmol, Aldrich). The mixture was cooledto −78° C., and a solution of DMSO (0.1 mL, 1.4 mmol) in DCM (0.5 mL)was added dropwise with stirring. The reaction mixture was stirred at−78° C. for 2 h, TFA (141 mg, 1.4 mmol) was added dropwise, and themixture was allowed to reach room temperature. The reaction mixture waspartitioned between water (10 mL) and DCM (10 mL). The organic phase wasseparated, washed with sat. aqueous solution of sodium bicarbonate,dried over Na₂SO₄ and filtered. The filtrate was evaporated underreduced pressure to give the crude title compound, which was used in thenext step without additional purification. MS (ESI, pos. ion) m/z: 459(M+1).

(b)N-(4-(2-(Piperidin-1-ylmethyl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide,trifluoroacetic acid salt.

The crude product from step (a) above reacted with piperidine (0.2 mL,Aldrich) under the conditions of Example 29(b) to give the titlecompound as salt with TFA. MS (ESI, pos. ion) m/z: 528 (M+1).

EXAMPLE 100

(S)-8-(2-((S)-1-(4-Fluorophenyl)ethylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-ylamino)-1,2,3,4-tetrahydronaphthalen-2-ol,trifluoroacetic acid salt and(R)-8-(2-((S)-1-(4-fluorophenyl)ethylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-ylamino)-1,2,3,4-tetrahydronaphthalen-2-ol,trifluoroacetic acid salt

(a)(R,S)-8-({2-Chloro-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol.

A mixture of 2,4-dichloro-6-(4-trifluoromethyl-phenyl)-pyrimidine (293mg, 1 mmol, Example 7(a)) and(R,S)-8-amino-1,2,3,4-tetrahydronaphthalen-2-ol (163 mg, 1 mmol,prepared as described in WO 2003/095240 A1) in EtOH (5 mL) was heated to70° C. for 16 h. The reaction mixture was evaporated in vacuo and theresidue was purified by silica gel column chromatography (40%EtOAc/hexane) to give the title compound. MS (ESI, pos. ion) m/z: 420(M+1).

(b)(S)-8-(2-((S)-1-(4-Fluorophenyl)ethylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-ylamino)-1,2,3,4-tetrahydronaphthalen-2-ol,trifluoroacetic acid salt and(R)-8-(2-((S)-1-(4-fluorophenyl)ethylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-ylamino)-1,2,3,4-tetrahydronaphthalen-2-ol,trifluoroacetic acid salt.

The reaction of(R,S)-8-({2-chloro-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-olfrom step (a) above (84 mg, 0.2 mmol) with(S)-1-(4-fluorophenyl)ethanamine (28 mg, 0.4 mmol, Aldrich) under theconditions of Example 34 provided, after purification by preparativeHPLC, the title compound as a diastereomeric mixture. MS (ESI, pos. ion)m/z: 523 (M+1).

EXAMPLE 101

2-(Dimethylamino)-N-(4-(2-acetamidobenzo[d]thiazol-4-yloxy)-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)acetamide,trifluoroacetic acid salt

(a)N-(4-(2-Amino-6-chloropyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide.

A mixture of 2-amino-4,6-dichloro-pyrimidine (0.98 g, 6.0 mmol,Aldrich), N-(4-hydroxybenzo[d]thiazol-2-yl)acetamide (1.3 g, 6.0 mmol,Example 7(c)) and K₂CO₃ (0.97 g, 7.0 mmol) in DMF (10 mL) was heated at60° C. for 16 h. The reaction mixture was cooled to room temperature,diluted with water (100 mL), and extracted with EtOAc (250 mL). TheEtOAc layer was separated, dried over Na₂SO₄, filtered, and concentratedin vacuo. Purification of the residue by silica gel columnchromatography (60% EtOAc/hexane) provided the title compound as anoff-white solid. MS (ESI, pos. ion.) m/z: 336 (M+1).

(b)N-(4-(2-Amino-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide.

A mixture ofN-(4-(2-amino-6-chloropyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamidefrom step (a) above (370 mg, 1.1 mmol),4-(trifluoromethyl)phenyl-boronic acid (304 mg, 1.6 mmol, Aldrich),PdCl₂(PPh₃)₂ (105 mg, 0.15 mmol, Aldrich), Na₂CO₃.H₂O (248 mg, 2.0mmol), dimethoxyethane (2.1 mL), H₂O (0.9 mL) and EtOH (0.6 mL) washeated in a microwave synthesizer at 125° C. with stirring for 10 min.The reaction mixture was diluted with water (25 mL) and extracted withEtOAc (2×30 mL). The combined organic extracts were washed with brine(20 mL), dried over Na₂SO₄, and filtered. The filtrate was concentratedin vacuo and the residue was purified by silica gel columnchromatography (40% EtOAc/hexane) to give the title compound as a solid.M.p.: 232-234° C. MS (ESI, pos. ion) m/z: 446 (M+1).

(c)2-(Dimethylamino)-N-(4-(2-acetamidobenzo[d]thiazol-4-yloxy)-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)acetamide,trifluoroacetic acid salt.

To a solution ofN-(4-(2-amino-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamidefrom step (b) above (89 mg, 0.2 mmol) in dioxane (4 mL) was added NaH(60% in mineral oil, 40 mg, 1 mmol, Aldrich) and the mixture was stirredat room temperature for 5 min. Dimethylaminoacetyl chloride HCl salt (79mg, 0.5 mmol, Lancaster) was added, and the reaction mixture was stirredfor 30 min at room temperature. The mixture was diluted with water (15mL) and extracted with EtOAc (40 mL). The organic phase was washed withbrine (10 mL), dried over Na₂SO₄, and filtered. The filtrate wasevaporated in vacuo and the residue purified by silica gel columnchromatography (10% MeOH/DCM) to give the crude product. Additionalpurification of the product by preparative HPLC [gradient 20-80% MeCN(0.1% TFA)/H₂O (0.1% TFA)] gave the title compound as a TFA salt. MS(ESI, pos. ion) m/z: 531 (M+1).

EXAMPLE 102

N-(4-(2-(1-(4-Fluorophenyl)ethoxy)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide

A mixture ofN-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzo[d]thiazol-2-yl}-acetamide(465 mg, 1.0 mmol, Example 7(d)), 4-fluoro-α-methylbenzyl-alcohol (140mg, 1 mmol, Aldrich), K₂CO₃ (207 mg, 1.5 mmol) and 85% MeSO₂Na (30 mg,0.25 mmol, Aldrich) in DMF (50 mL) was heated at 120° C. with stirringfor 5 h. The reaction mixture was allowed to reach room temperature andwas diluted with water (50 mL), and exacted with EtOAc (2×50 mL). Theorganic phase was washed with brine (10 mL), dried over Na₂SO₄, andfiltered. The filtrate was evaporated in vacuo and the residue purifiedby silica gel column chromatography (20% EtOAc/hexane) to give the titlecompound. MS (ESI, pos. ion) m/z: 569 (M+1).

EXAMPLE 103

4-(2-(1-Ethylpiperidin-3-yloxy)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-amine

A mixture ofN-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzo[d]thiazol-2-yl}-acetamide(70 mg, 0.15 mmol, Example 7(d)) and 1-ethyl-3-hydroxypiperidine (39 mg,0.3 mmol, Aldrich) in ethanol (1 mL) was heated in a microwavesynthesizer at 140° C. for 20 min. The reaction mixture was diluted withsat. aqueous solution of NaHCO₃ (10 mL) and extracted with EtOAc (2×30mL). The combined organic extracts were washed with brine (20 mL), driedover Na₂SO₄, and filtered. The filtrate was concentrated in vacuo andthe residue was purified by preparative HPLC [gradient 20-80% MeCN (0.1%TFA)/H₂O (0.1% TFA)] to give the title compound as a salt with TFA. MS(ESI, pos. ion) m/z: 516 (M+1).

EXAMPLE 104

N-(4-(6-(4-((R)-1-(4-Fluorophenyl)ethyl)piperazin-1-yl)-2-(((S)-tetrahydrofuran-2-yl)methylamino)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamideandN-(4-(6-(4-((R)-1-(4-fluorophenyl)ethyl)piperazin-1-yl)-2-(((R)-tetrahydrofuran-2-yl)methylamino)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide

(a) 4,6-Dichloro-N-((tetrahydrofuran-2-yl)methyl)pyrimidin-2-amine and2,6-dichloro-N-((tetrahydrofuran-2-yl)methyl)pyrimidin-4-amine.

A mixture of tetrahydrofurfurylamine (0.81 g, 8 mmol, Aldrich) and2,4,6-trichloro-pyrimidine (1.46 g, 8 mmol, Aldrich) in EtOH (5 mL) washeated at 60° C. for 3 h. The reaction mixture was left to reach roomtemperature and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (35% EtOAc/hexane) to givethe fast running4,6-dichloro-N-((tetrahydrofuran-2-yl)methyl)pyrimidin-2-amine [MS (ESI,pos. ion) m/z: 248 (M+1)] and2,6-dichloro-N-((tetrahydrofuran-2-yl)methyl)pyrimidin-4-amine [MS (ESI,pos. ion) m/z: 248 (M+1)].

(b)N-(4-(6-Chloro-2-((tetrahydrofuran-2-yl)methylamino)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide.

A mixture of4,6-dichloro-N-((tetrahydrofuran-2-yl)methyl)pyrimidin-2-amine from step(a) above (248 mg, 1.0 mmol), N-(4-hydroxy-benzothiazol-2-yl)-acetamide(208 mg, 1.0 mmol, Example 7(c)) and K₂CO₃ (138 mg, 1.0 mmol) in DMF (5mL) was heated at 90° C. for 6 h. The reaction mixture was cooled toroom temperature and partitioned between EtOAc (100 mL) and water (40mL). The EtOAc layer was separated, dried over Na₂SO₄, filtered, andconcentrated in vacuo. Purification of the residue by silica gel columnchromatography (40% EtOAc/hexane) provided the title compound as a whitesolid. MS (ESI, pos. ion.) m/z: 420 (M+1).

(c)N-(4-(6-(4-((R)-1-(4-Fluorophenyl)ethyl)piperazin-1-yl)-2-(((S)-tetrahydrofuran-2-yl)methylamino)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamideandN-(4-(6-(4-((R)-1-(4-fluorophenyl)ethyl)piperazin-1-yl)-2-(((R)-tetrahydrofuran-2-yl)methylamino)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide.

A mixture ofN-(4-(6-chloro-2-((tetrahydrofuran-2-yl)methylamino)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamidefrom step (b) above (126 mg, 0.3 mmol) and(R)-1-(1-(4-fluorophenyl)ethyl)piperazine (125 mg, 0.6 mmol, prepared asdescribed in US 2005/0176726A1) in ethanol (1 mL) was heated in amicrowave synthesizer at 160° C. for 40 min. The reaction mixture wasdiluted with sat. aqueous solution of NaHCO₃ (10 mL) and extracted withEtOAc (2×20 mL). The combined organic extracts were washed with brine(20 mL), dried over Na₂SO₄, and filtered. The filtrate was concentratedin vacuo and the residue was purified by silica gel columnchromatography (4% MeOH/DCM) to provide the title compound as a mixtureof diastereoisomers. MS (ESI, pos. ion) m/z: 592 (M+1).

EXAMPLE 105

3-Amino-5-(6-(4-((R)-1-(4-fluorophenyl)ethyl)piperazin-1-yl)-2-(((S)-tetrahydrofuran-2-yl)methylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-oneand3-amino-5-(6-(4-((R)-1-(4-fluorophenyl)ethyl)piperazin-1-yl)-2-(((R)-tetrahydrofuran-2-yl)methylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one

(a)3-Amino-5-(6-chloro-2-((tetrahydrofuran-2-yl)methylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one.

A mixture of4,6-dichloro-N-((tetrahydrofuran-2-yl)methyl)pyrimidin-2-amine (99 mg,0.4 mmol, Example 104(a)), 3-amino-5-hydroxyquinoxalin-2(1H)-one (71 mg,0.4 mmol, prepared as described in WO 2004/014871) and Cs₂CO₃ (130 mg,4.0 mmol) in DMF (3 mL) was heated at 70° C. for 16 h. The reactionmixture was cooled to room temperature and was partitioned between EtOAc(30 mL) and water (20 mL). The EtOAc layer was separated, dried overNa₂SO₄, filtered, and concentrated in vacuo. Purification of the residueby silica gel column chromatography (40% EtOAc/hexane) provided thetitle compound as a white solid. MS (ESI, pos. ion.) m/z: 389 (M+1).

(b)3-Amino-5-(6-(4-((R)-1-(4-fluorophenyl)ethyl)piperazin-1-yl)-2-(((S)-tetrahydrofuran-2-yl)methylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-oneand3-amino-5-(6-(4-((R)-1-(4-fluorophenyl)ethyl)piperazin-1-yl)-2-(((R)-tetrahydrofuran-2-yl)methylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one.

The reaction of3-amino-5-(6-chloro-2-((tetrahydrofuran-2-yl)methylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-onefrom step (a) above (78 mg, 0.2 mmol) with(R)-1-(1-(4-fluorophenyl)ethyl)piperazine (83 mg, 0.4 mmol, prepared asdescribed in US 2005/0176726A1) under the conditions of Example 104(c)provided the title compound as a mixture of diastereoisomers. MS (ESI,pos. ion) m/z: 561 (M+1).

EXAMPLE 106

3-Amino-5-(2-(1-(4-fluorophenyl)ethylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one

(a)3-Amino-5-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one.

The reaction of 2,4-dichloro-6-(4-trifluoromethyl-phenyl)-pyrimidine(293 mg, 1.0 mmol, Example 7(a)) with3-amino-5-hydroxyquinoxalin-2(1H)-one (127 mg, 1.0 mmol, prepared asdescribed in WO 2004/014871) under the conditions of Example 7(d)provided the title compound as a solid. M.p.: 434° C. MS (ESI, pos. ion)m/z: 423 (M+1).

(b)3-Amino-5-(2-(1-(4-fluorophenyl)ethylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one.

The reaction of3-amino-5-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-onefrom step (a) above (108 mg, 0.25 mmol) with4-fluoro-alpha-methylbenzylamine (70 mg, 0.5 mmol, Aldrich) under theconditions of Example 34 provided the title compound as an amorphoussolid. MS (ESI, pos. ion) m/z: 537 (M+1). TABLE 8 The following exampleswere prepared from3-amino-5-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one (Example 106(a)) and commercially availableamines according to the procedure described for the preparation ofExample 34, or with slight modifications to that procedure. MeltingExample Point Mass Spec. # Structure (° C.) (ESI) m/z 107

amorphous solid 568 (M + 1) 108

amorphous solid 528 (M + 1) 109

241 487 (M + 1) 110

amorphous solid 540 (M + 1) 111

amorphous solid 520 (M + 1) 112

amorphous solid 506 (M + 1) 113

289 520 (M + 1) 114

243 487 (M + 1) 115

amorphous solid 556 116

>300   598 (M + 1) 117

>300   562 (M + 1)

EXAMPLE 118

3-Amino-5-(2-((1-neopentylpiperidin-2-yl)methylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one,trifluoroacetic acid salt

(a) Piperidine-2-carboxamide.

A mixture of methyl pipecolinate hydrochloride (15.0 g, 83 mmol,Aldrich) and 8% aqueous solution of ammonium hydroxide (150 mL) wasstirred for 18 h at room temperature. The white precipitate was filteredand the filter cake was washed with water, and dried under vacuo to givethe title compound. MS (ESI, pos. ion) m/z: 129 (M+1).

(b) 1-Neopentylpiperidine-2-carboxamide.

A mixture of piperidine-2-carboxamide from step (a) above (0.4 g, 3mmol), trimethylacetaldehyde (0.8 mL, 9 mmol, Aldrich) and NaBH(OAc)₃ (3g, 15 mmol, Aldrich) in DCM (10 mL) was stirred for 1 h at roomtemperature. The reaction mixture was evaporated under reduced pressureand the residue was diluted with sat. aqueous solution of NaHCO₃ (10 mL)and extracted with EtOAc 2×20 mL). The combined organic extracts werewashed with brine (20 mL), dried over Na₂SO₄, and filtered. The filtratewas evaporated in vacuo to give the title compound. MS (ESI, pos. ion)m/z: 199 (M+1).

(c) (1-Neopentylpiperidin-2-yl)methanamine.

The reaction of 1-neopentylpiperidine-2-carboxamide from step (b) above(0.3 g, 1.5 mmol) with LiAlH₄ under the conditions of Example 72(a)provided the title compound as yellow oil. MS (ESI, pos. ion) m/z: 185(M+1).

(d)3-Amino-5-(2-((1-neopentylpiperidin-2-yl)methylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one,trifluoroacetic acid salt.

The reaction of3-amino-5-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one(43 mg, 0.1 mmol, Example 106(a)) with(1-neopentylpiperidin-2-yl)methanamine from step (c) above (37 mg, 0.2mmol) under the conditions of Example 34 provided the crude product. Theproduct was purified by silica gel column chromatography (20% MeOH/DCM),and then by preparative HPLC [gradient 20-80% MeCN (0.1% TFA)/H₂O (0.1%TFA)] to give the title compound as a salt with TFA. MS (ESI, pos. ion)m/z: 582 (M+1).

EXAMPLE 119

(S)-3-Amino-5-(2-(isobutyl((1-isobutylpiperidin-2-yl)methyl)amino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one,trifluoroacetic acid salt

(a) (S)-N-((1-Isobutylpiperidin-2-yl)methyl)-2-methylpropan-1-amine.

A mixture of (S)-tert-butyl piperidin-2-ylmethylcarbamate (1.07 g, 5mmol, Astatech) and 50% TFA in DCM (10 mL) was stirred at roomtemperature for 30 min. The reaction mixture was evaporated underreduced pressure and the residue was dried under vacuo for 16 h. Theresidue was dissolved in DCM (10 mL), isobutyraldehyde (1.44 g, 20 mmol)and NaBH(OAc)₃ (4.22 g, 20 mmol, Aldrich) were added, and the mixturewas stirred for 1 h at room temperature. The reaction mixture wasevaporated under reduced pressure and the residue was diluted with sat.aqueous solution of NaHCO₃ (100 mL) and extracted with EtOAc (2×75 mL).The combined organic extracts were washed with brine (20 mL), dried overNa₂SO₄, and filtered. The filtrate was evaporated in vacuo and theresidue was purified by silica gel chromatography (MeOH) to give thetitle compound. MS (ESI, pos. ion) m/z: 227 (M+1).

(b)(S)-3-Amino-5-(2-(isobutyl((1-isobutylpiperidin-2-yl)methyl)amino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one,trifluoroacetic acid salt.

The reaction of3-amino-5-(6-chloro-2-((tetrahydrofuran-2-yl)methylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one(87 mg, 0.2 mmol, Example 106(a)) with(S)-N-((1-isobutylpiperidin-2-yl)methyl)-2-methylpropan-1-amine fromstep (a) above (91 mg, 0.4 mmol) under the conditions of Example 34provided the crude product. The product was purified by silica gelcolumn chromatography (6% MeOH/DCM), and then by preparative HPLC[gradient 20-80% MeCN (0.1% TFA)/H₂O (0.1% TFA)] to give the titlecompound. MS (ESI, pos. ion) m/z: 624 (M+1).

EXAMPLE 120

(S)-3-Amino-5-(2-((1-isobutylpiperidin-2-yl)methylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one

(a) (S)-Piperidine-2-carboxamide.

A mixture of (S)-tert-butyl 2-carbamoylpiperidine-1-carboxylate (5.0 g,22 mmol, Astatech) and 50% TFA in DCM (25 mL) was stirred for 3 h atroom temperature. The reaction mixture was evaporated under reducedpressure and the residue was dissolved in DCM (70 mL). The solution waswashed with 1N NaOH (25 mL) and brine (25 mL), dried over Na₂SO₄, andfiltered. The filtrate was evaporated under reduced pressure and theresidue was dried in vacuo to give the title compound. MS (ESI, pos.ion) m/z: 129 (M+1).

(b) (S)-1-Isobutylpiperidine-2-carboxamide.

The reaction of (S)-piperidine-2-carboxamide from step (a) above (1.0 g,5.4 mmol) with isobutyraldehyde (2.4 g, 33 mmol, Aldrich) under theconditions of Example 118(b) provided the title compound. MS (ESI, pos.ion) m/z: 185 (M+1).

(c) (S)-(1-Isobutylpiperidin-2-yl)methanamine.

The reaction of (S)-1-isobutylpiperidine-2-carboxamide from step (b)above (0.8 g, 4.7 mmol) with LiAlH₄ under the conditions of Example72(a) provided the title compound. MS (ESI, pos. ion) m/z: 171 (M+1).

(d)(S)-3-Amino-5-(2-((1-isobutylpiperidin-2-yl)methylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one.

The reaction of3-amino-5-(6-chloro-2-((tetrahydrofuran-2-yl)methylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one(87 mg, 0.2 mmol, Example 106(a)) with(S)-(1-isobutylpiperidin-2-yl)methanamine from step (c) above (68 mg,0.4 mmol) under the conditions of Example 34 provided the title compoundas a solid. M.p.: 228° C. MS (ESI, pos. ion) m/z: 568 (M+1).

EXAMPLE 121

(R)-3-Amino-5-(2-((1-isobutylpiperidin-2-yl)methylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one

Separation of the enantiomers of(R,S)-3-amino-5-(2-((1-isobutylpiperidin-2-yl)methylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one(Example 107) on a chiral column provided(S)-3-amino-5-(2-((1-isobutylpiperidin-2-yl)methylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one(Example 120(d)) and the title compound as a solid. M.p.: 229° C. MS(ESI, pos. ion) m/z: 568 (M+1).

EXAMPLE 122

3-Amino-5-(6-(4-((S)-1-(4-fluorophenyl)ethyl)piperazin-1-yl)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one, trifluoroacetic acid salt

(a) (S)-4,6-Dichloro-N-(1-methoxypropan-2-yl)pyrimidin-2-amine and(S)-2,6-dichloro-N-(1-methoxypropan-2-yl)pyrimidin-4-amine.

The reaction of 2,4,6-trichloropyrimidine (5 ml, 25 mmol, Aldrich) with(S)-1-methoxypropan-2-amine (2 g, 25 mmol, Lancaster) under theconditions of Example 104(a) provided the crude mixture of products. Themixture was purified by silica gel column chromatography (15%EtOAc/hexane) to give the fast running(S)-4,6-dichloro-N-(1-methoxypropan-2-yl)pyrimidin-2-amine [MS (ESI,pos. ion) m/z: 236 (M+1)] and(S)-2,6-dichloro-N-(1-methoxypropan-2-yl)pyrimidin-4-amine MS (ESI, pos.ion) m/z: 236 (M+1).

(b)(S)-3-Amino-5-(6-chloro-2-(1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one

The reaction of(S)-4,6-dichloro-N-(1-methoxypropan-2-yl)pyrimidin-2-amine from step (a)above (0.62 g, 2.63 mmol) with 3-amino-5-hydroxyquinoxalin-2(1H)-one(0.47 g, 3 mmol, prepared as described in WO 2004/014871) under theconditions of Example 105(a) provided the title compound as an off-whitesolid. MS (ESI, pos. ion.) m/z: 377 (M+1).

(c)3-Amino-5-(6-(4-((S)-1-(4-fluorophenyl)ethyl)piperazin-1-yl)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one,trifluoroacetic acid salt.

The reaction of(S)-3-amino-5-(6-chloro-2-(1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-onefrom step (b) above (75 mg, 0.2 mmol) with(S)-1-(1-(4-fluorophenyl)ethyl)piperazine (42 mg, 0.2 mmol, prepared asdescribed in US 2005/0176726A1) under the condition of Example 104(c)provided the crude product, which was purified by preparative HPLC[gradient 20-80% MeCN (0.1% TFA)/H₂O (0.1% TFA)] to give the titlecompound. MS (ESI, pos. ion) m/z: 549 (M+1).

EXAMPLE 123

3-Amino-5-(6-(4-((R)-1-(4-fluorophenyl)ethyl)piperazin-1-yl)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one

The reaction of(S)-3-amino-5-(6-chloro-2-(1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one(75 mg, 0.2 mmol, Example 122(b)) with(R)-1-(1-(4-fluorophenyl)ethyl)piperazine (42 mg, 0.2 mmol, prepared asdescribed in US 2005/0176726A1) under the condition of Example 104(c)provided the title compound. MS (ESI, pos. ion) m/z: 549 (M+1).

EXAMPLE 124

(R)-3-Amino-5-(6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)-2-(2-methoxyethylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one

(a) 4,6-Dichloro-N-(2-methoxyethyl)pyrimidin-2-amine and2,6-dichloro-N-(2-methoxyethyl)pyrimidin-4-amine.

The reaction of 2,4,6-trichloropyrimidine (2.0 g, 16 mmol, Aldrich) with2-methoxyethylamine (1.2 g, 16 mmol, Lancaster) under the conditions ofExample 104(a) provided the crude mixture of products. The mixture waspurified by silica gel column chromatography (15% EtOAc/hexane) to givethe fast running 4,6-dichloro-N-(2-methoxyethyl)pyrimidin-2-amine [MS(ESI, pos. ion) m/z: 223 (M+1)] and2,6-dichloro-N-(2-methoxyethyl)pyrimidin-4-amine [MS (ESI, pos. ion)m/z: 223 (M+1)].

(b)3-Amino-5-(6-chloro-2-(2-methoxyethylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one.

The reaction of 4,6-dichloro-N-(2-methoxyethyl)pyrimidin-2-amine fromstep (a) above (0.5 g, 2.25 mmol) with3-amino-5-hydroxyquinoxalin-2(1H)-one (0.4 g, 2.25 mmol, prepared asdescribed in WO 2004/014871) under the conditions of Example 105(a)provided the title compound as an off-white solid. MS (ESI, pos. ion.)m/z: 363 (M+1).

(c)(R)-3-Amino-5-(6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)-2-(2-methoxyethylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one.

The reaction of3-amino-5-(6-chloro-2-(2-methoxyethylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-onefrom step (b) above (135 mg, 0.37 mmol) with(S)-1-(1-(4-fluorophenyl)ethyl)piperazine (155 mg, 0.74 mmol, preparedas described in US 2005/0176726A1) under the condition of Example 104(c)provided the crude product, which was purified by preparative HPLC[gradient 20-80% MeCN (0.1% TFA)/H₂O (0.1% TFA)] to give the titlecompound as an amorphous solid. MS (ESI, pos. ion) m/z: 535 (M+1).

EXAMPLE 125

3-Amino-5-(6-(2-amino-4-(trifluoromethyl)phenyl)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one

(a) 2-(tert-Butoxycarbonyl)-4-(trifluoromethyl)phenylboronic acid.

To a solution of (3-trifluoromethylphenyl)carbamic acid tert-butyl ester(15 g, 57 mmol, Aldrich) in THF (400 mL) was added sec-BuLi (100 mL, 1.3M in cyclohexane, Aldrich) dropwise over 20 min with stirring at −40° C.The mixture was stirred for 1 h at −40° C. and cooled to −78° C.Trimethyl borate (26 mL, 230 mmol, Aldrich) was added dropwise over 10min with stirring at −78° C. The reaction mixture was allowed to warm toroom temperature, and then stirred at room temperature for 0.5 h. Thereaction mixture was quenched with 1M aqueous solution of NaH₂PO₄ (200mL) and H₂O (200 mL). The mixture was concentrated under reducedpressure, and the aqueous residue was extracted with EtOAc (2×250 mL).The combined extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuum to give the title compound as yellowfoam, which was used in the next step without additional purification.

(b)3-Amino-5-(6-(2-amino-4-(trifluoromethyl)phenyl)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one.

The reaction of 2-(tert-butoxycarbonyl)-4-(trifluoromethyl)phenylboronicacid from step (a) above (413 mg, 1.35 mmol) with(S)-3-amino-5-(6-chloro-2-(1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one(340 mg, 0.9 mmol, Example 122(b)) under the conditions of Example 32provided the title compound as an amorphous solid. MS (ESI, pos. ion)m/z: 502 (M+1).

EXAMPLE 126

tert-Butyl 2-(6-(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yloxy)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yl)-5-(trifluoromethyl)phenylcarbamate

The title compound was formed as a side product of the reactiondescribed in Example 125(b) and was isolated as an amorphous solid. MS(ESI, pos. ion) m/z: 602 (M+1).

EXAMPLE 127

(2S,5R)-tert-Butyl2-((2-(6-(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yloxy)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)carbamoyl)-5-methylpyrrolidine-1-carboxylateand (2S,5S)-tert-butyl2-((2-(6-(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yloxy)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)carbamoyl)-5-methylpyrrolidine-1-carboxylate

To a mixture of3-amino-5-(6-(2-amino-4-(trifluoromethyl)phenyl)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one(85 mg, 0.17 mmol, Example 125(b)) and (2S,5R,S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (39mg, 0.17 mmol, AnaSpec) in CH₂Cl₂ (5 mL) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (40 mg,0.21 mmol, Aldrich) at 25 ° C. The reaction mixture was stirred at 25°C. for 16 h and partitioned between 1:1 mixture of EtOAc/H₂O. Theorganic phase was separated, washed with H₂O and brine, dried overNa₂SO₄, filtered and evaporated under reduced pressure. Purification ofthe residue by silica gel column chromatography (40% EtOAc/hexane)afforded the title compound as a mixture of diastereoisomers. MS (ESI,pos. ion) m/z: 713 (M+1).

EXAMPLE 128

(2S,5R)-N-(2-(6-(3-Amino-2-oxo-1,2-dihydroquinoxalin-5-yloxy)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)-5-methylpyrrolidine-2-carboxamide,trifluoroacetic acid salt and(2S,5S)-N-(2-(6-(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yloxy)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)-5-methylpyrrolidine-2-carboxamide,trifluoroacetic acid salt

The reaction of the mixture of diastereoisomers (2S,5R)-tert-butyl2-((2-(6-(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yloxy)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)carbamoyl)-5-methylpyrrolidine-1-carboxylateand (2S,5S)-tert-butyl2-((2-(6-(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yloxy)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)carbamoyl)-5-methylpyrrolidine-1-carboxylate (35 mg 0.05 mmol, Example 127) with 1:1 mixture oftrifluoroacetic acid/DCM (3 mL) under the conditions of Example 34afforded the title compound as a mixture of diastereoisomers. MS (ESI,pos. ion) m/z: 713 (M+1).

EXAMPLE 129

8-(2-(1-(4-Fluorophenyl)ethylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinolin-2-amine

(a)8-(2-Chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinolin-2-amine.

The reaction of 2,4-dichloro-6-(4-trifluoromethyl-phenyl)-pyrimidine(0.5 g, 1.71 mmol, Example 7(a)) with 2-aminoquinolin-8-ol (0.27 g, 1.71mmol, Sigma) under the conditions of Example 7(d) provided the titlecompound as an amorphous solid. MS (ESI, pos. ion) m/z: 417 (M+1).

(b)8-(2-(1-(4-Fluorophenyl)ethylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinolin-2-amine.

The reaction of8-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinolin-2-aminefrom step (a) above (42 mg, 0.1 mmol) with4-fluoro-alpha-methylbenzylamine (14 mg, 0.1 mmol, Aldrich) under theconditions of Example 34 provided the title compound. MS (ESI, pos. ion)m/z: 520 (M+1).

EXAMPLE 130

8-(2-((1-Isobutylpiperidin-2-yl)methylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinolin-2-amine,trifluoroacetic acid salt

The reaction of8-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinolin-2-amine(42 mg, 0.1 mmol, Example 129(a)) with 4-fluoro-alpha-methylbenzylamine(17 mg, 0.1 mmol) under the conditions of Example 34 provided the titlecompound as an amorphous solid. MS (ESI, pos. ion) m/z: 551 (M+1).

EXAMPLE 131

tert-Butyl4-(4-(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yloxy)-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)-2-fluorophenylcarbamate

The reaction of3-amino-5-(6-chloro-2-((tetrahydrofuran-2-yl)methylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one(217 mg, 0.5 mmol, Example 106(a)) with4-N-Boc-amino-3-fluorophenylboronic acid (191 mg, 0.75 mmol, AstaTech),under the conditions of Example 32 provided the title compound. MS (ESI,pos. ion) m/z: 609 (M+1).

EXAMPLE 132

3-Amino-5-(2-(4-amino-3-fluorophenyl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one

The title compound was obtained as a side product of the reactiondescribed in Example 131 and was isolated as an amorphous solid. MS(ESI, pos. ion) m/z: 509 (M+1).

EXAMPLE 133

tert-Butyl2-((4-(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yloxy)-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-ylamino)methyl)piperidine-1-carboxylate

The reaction of3-amino-5-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one(433 mg, 1.0 mmol, Example 106(a)) with tert-butyl2-(aminomethyl)piperidine-1-carboxylate (428 mg, 2 mmol, Fluorochem)under the conditions of Example 34 provided the title compound as anamorphous solid. MS (ESI, pos. ion) m/z: 612 (M+1).

EXAMPLE 134

3-Amino-5-(2-((1-(cyclopropylmethyl)piperidin-2-yl)methylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one

(a)3-Amino-5-(2-(piperidin-2-ylmethylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one.

The reaction of tert-butyl2-((4-(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yloxy)-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-ylamino)methyl)piperidine-1-carboxylate(Example 133) with 1:1 mixture of trifluoroacetic acid/DCM under theconditions of Example 35 afforded the title compound as an amorphoussolid, which was used in the next step without additional purification.MS (ESI, pos. ion) m/z: 512 (M+1).

(b)3-Amino-5-(2-((1-(cyclopropylmethyl)piperidin-2-yl)methylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one.

The reaction of3-amino-5-(2-(piperidin-2-ylmethylamino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-onefrom step (a) above (114 mg, 0.2 mmol) with cyclopropanecarboxaldehyde(70 mg, 1.0 mmol, Aldrich) under the conditions of Example 36 providedthe title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 566(M+1).

EXAMPLE 135

3-Amino-5-(2-(piperazin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one

The reaction of3-amino-5-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one(180 mg, 1.0 mmol, Example 106(a)) with piperazine (71 mg, 2.0 mmol,Aldrich) under the conditions of Example 34 afforded the title compoundas an amorphous solid. MS (ESI, pos. ion) m/z: 484 (M+1).

EXAMPLE 136

3-Amino-5-(2-(4-(cyclopropylmethyl)piperazin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one

The reaction of3-amino-5-(2-(piperazin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one(27 mg, 0.056 mmol, Example 135) with cyclopropanecarboxaldehyde (59 mg,0.279 mmol, Aldrich) under the conditions of Example 36 provided thetitle compound as an amorphous solid. MS (ESI, pos. ion) m/z: 538 (M+1).

EXAMPLE 137

3-Amino-5-(2-(4-isobutylpiperazin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one

The reaction of3-amino-5-(2-(piperazin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one(97 mg, 0.2 mmol, Example 135) with isobutyraldehyde (43 mg, 0.6 mmol,Aldrich) under the conditions of Example 36 provided the title compoundas an amorphous solid. MS (ESI, pos. ion) m/z: 540 (M+1).

EXAMPLE 138

3-Amino-5-(6-((S)-3-isobutyl-4-(2,2,2-trifluoroethyl)piperazin-1-yl)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one

(a) (S)-2-Isobutyl-1-(2,2,2-trifluoroethyl)piperazine.

(b)3-Amino-5-(6-((S)-3-isobutyl-4-(2,2,2-trifluoroethyl)piperazin-1-yl)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one.

The reaction of(S)-3-amino-5-(6-chloro-2-(1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one(74 mg, 0.2 mmol, Example 122(b)) with(S)-2-isobutyl-1-(2,2,2-trifluoroethyl)piperazine (89 mg, 0.4 mmol)under the conditions of Example 34 provided the title compound as anamorphous solid. MS (ESI, pos. ion) m/z: 565 (M+1).

EXAMPLE 139

(S)-tert-Butyl4-(6-(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yloxy)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yl)-2-isobutylpiperazine-1-carboxylate

The reaction of(S)-3-amino-5-(6-chloro-2-(1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one(74 mg, 0.2 mmol, Example 122(b)) with (S)-tert-butyl2-isobutylpiperazine-1-carboxylate (48 mg, 0.2 mmol, CNH-Tech) under theconditions of Example 34 provided the title compound as an amorphoussolid. MS (ESI, pos. ion) m/z: 583 (M+1).

EXAMPLE 140

5-(6-(2-(3,4-Dimethoxybenzylamino)-6-(trifluoromethyl)pyridin-3-yl)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)-3-aminoquinoxalin-2(1H)-one,trifluoroacetic acid salt

(a) (S)-4,6-Diiodo-N-(1-methoxypropan-2-yl)pyrimidin-2-amine

A mixture of (S)-4,6-dichloro-N-(1-methoxypropan-2-yl)pyrimidin-2-amine(260 mg, 0.11 mmol, Example 122(a)), hydriodic acid (57 wt. % in water,40.4 μl, 0.165 mmol, Aldrich), sodium iodide (248 mg, 0.165 mmol) andDCM (5 mL) was stirred at room temperature for 2 h. The reaction mixturewas diluted with EtOAc (50 mL), washed with 1N NaOH (2×25 mL) and brine(60 mL), dried over Na₂SO₄ and filtered. The filtrate was evaporatedunder reduced pressure and the residue was purified by silica gel columnchromatography (7% EtOAc/hexane) to give the title compound. MS (ESI,pos. ion) m/z: 420 (M+1).

(b)(S)-3-Amino-5-(6-iodo-2-(1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one.

A mixture of 4,6-diiodo-N-(2-methoxyethyl)pyrimidin-2-amine from step(a) above (330 mg, 0.79 mmol), 3-amino-5-hydroxyquinoxalin-2(1H)-one(140 mg, 0.79 mmol, prepared as described in WO 2004/014871), cesiumcarbonate (513 mg, 1.58 mmol, Aldrich) and DMF (5 mL) was heated at 90°C. with stirring for 16 h. The reaction mixture was left to reach roomtemperature and was diluted with water (40 mL), and extracted with EtOAc(×2). The combined organic extracts were washed with brine, dried overNa₂SO₄ and filtered. The filtrate was evaporated under reduced pressureand the residue was purified by silica gel column chromatography (65%EtOAc/hexane) to give the title compound. MS (ESI, pos. ion) m/z: 469(M+1).

(c) 2-Chloro-3-tributylstannyl-6-trifluoromethyl-pyridine.

To a solution of diisopropylamine (5.5 mL, 39 mmol, Aldrich,) in THF (30mL) was added n-BuLi (15.6 mL, 2.5 M in hexanes, 39 mmol, Aldrich) withstirring at −78° C. The mixture was stirred at −78° C. for 30 min and atroom temperature for 15 min. The reaction mixture was cooled again to−78° C. and a solution of 2-chloro-6-trifluoromethylpyridine (5.0 g,27.5 mmol, Lancaster) in THF (20 mL) was added. The mixture was stirredat −78° C. for 1 h, tributyltin chloride (9 mL, 33 mmol, Aldrich) wasadded via a syringe, and stirring was continued for 2 h. The reactionmixture was allowed to reach 0° C., quenched with a sat. aqueoussolution of NH₄Cl, and extracted with Et₂O (3×). The combined organicextracts were dried over MgSO₄, filtered, and concentrated under reducedpressure. Purification of the residue by flash silica gel chromatography(gradient: 0-1% EtOAc/hexane) afforded the title compound as colorlessoil. MS (ESI, pos. ion.) m/z: 471 (M+1).

(d)3-Amino-5-(6-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one.

A mixture of 2-chloro-3-tributylstannyl-6-trifluoromethyl-pyridine fromstep (c) above (301 mg, 0.64 mmol),(S)-3-amino-5-(6-iodo-2-(1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-onefrom step (b) above (200 mg, 0.43 mmol), CuI (33 mg, 0.13 mmol,Aldrich), Pd(PPh₃)₄ (50 mg, 0.06 mmol, Aldrich) and DMF (5 mL) wasstirred at 100° C. for 3 h under N₂ atmosphere. The reaction mixture wasleft to reach room temperature and was diluted with EtOAc (30 mL). Themixture was washed with 10% Na₂CO₃ (20 mL) and brine (30 mL), dried overMgSO₄, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (gradient 20-60%EtOAc/hexane) to give the title compound. MS (ESI, pos. ion) m/z: 522(M+1).

(e)5-(6-(2-(3,4-Dimethoxybenzylamino)-6-(trifluoromethyl)pyridin-3-yl)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)-3-aminoquinoxalin-2(1H)-one,trifluoroacetic acid salt.

A mixture of3-amino-5-(6-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-onefrom step (d) above (130 mg, 0.25 mmol) and(3,4-dimethoxyphenyl)methanamine (83.3 mg, 0.50 mmol, Aldrich) in DMSO(2 mL) was heated in a microwave synthesizer at 120° C. for 40 min. Thereaction mixture was cooled to room temperature and the volatiles wereevaporated in vacuo. The residue was purified by preparative HPLC[gradient 20-80% MeCN (0.1% TFA)/H₂O (0.1% TFA)] to give the titlecompound as a salt with TFA. MS (ESI, pos. ion) m/z: 653 (M+1).

EXAMPLE 141

3-Amino-5-(6-(2-amino-6-(trifluoromethyl)pyridin-3-yl)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one,trifluoroacetic acid salt

A mixture of5-(6-(2-(3,4-dimethoxybenzylamino)-6-(trifluoromethyl)pyridin-3-yl)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)-3-aminoquinoxalin-2(1H)-one(120 mg, 0.18 mmol, Example 140) and 80% TFA/DCM (2 mL) was stirred atroom temperature for 6 h. The reaction mixture was evaporated underreduced pressure and the residue was purified by preparative HPLC[gradient 20-80% MeCN (0.1% TFA)/H₂O (0.1% TFA)] to give the titlecompound as a salt with TFA. MS (ESI, pos. ion) m/z: 488 (M+1).

Capsaicin-Induced Ca2+ Influx in Primary Dorsal Root Ganglion Neurons

Embryonic, 19 day old (E 19) dorsal root ganglia (DRG) were dissectedfrom timed-pregnant, terminally anesthetized Sprague-Dawley rats(Charles River, Wilmington, Mass.) and collected in ice-cold L-15 media(Life Technologies, Grand Island, N.Y.) containing 5% heat inactivatedhorse serum (Life Technologies). The DRG were then dissociated intosingle cell suspension using a papain dissociation system (WorthingtonBiochemical Corp., Freehold, N.J.). The dissociated cells were pelletedat 200×g for 5 min and re-suspended in EBSS containing 1 mg/mL ovomucoidinhibitor, 1 mg/mL ovalbumin and 0.005% DNase. Cell suspension wascentrifuged through a gradient solution containing 10 mg/mL ovomucoidinhibitor, 10 mg/mL ovalbumin at 200×g for 6 min to remove cell debris;and filtered through a 88 μm nylon mesh (Fisher Scientific, Pittsburgh,Pa.) to remove any clumps. Cell number was determined with ahemocytometer and cells were seeded into poly-ornithine 100 μg/mL(Sigma) and mouse laminin 1 μg/mL (Life Technologies)-coated 96-wellplates at 10×10³ cells/well in complete medium. The complete mediumconsists of minimal essential medium (MEM) and Ham's F12, 1:1,penicillin (100 U/mL), and streptomycin (100 μg/mL), and nerve growthfactor (10 ng/mL), 10% heat inactivated horse serum (Life Technologies).The cultures were kept at 37° C., 5% CO₂ and 100% humidity. Forcontrolling the growth of non-neuronal cells, 5-fluoro-2′-deoxyuridine(75 μM) and uridine (180 μM) were included in the medium. Activation ofVR1 is achieved in these cellular assays using either a capsaicinstimulus (ranging from 0.01-10 μM) or by an acid stimulus (addition of30 mM Hepes/Mes buffered at pH 4.1). Compounds are also tested in anassay format to evaluate their agonist properties at VR1.

Capsaicin Antagonist Assay:

E-19 DRG cells at 5 days in culture are incubated with serialconcentrations of VR1 antagonists, in HBSS (Hanks buffered salinesolution supplemented with BSA 0.1 mg/mL and 1 mM Hepes at pH 7.4) for15 min, 37° C. Cells are then challenged with a VR1 agonist, capsaicin200 nM, in activation buffer containing 0.1 mg/mL BSA, 15 mM Hepes, pH7.4, and 10 μCi/mL ⁴⁵Ca²⁺ (Amersham) in Ham's F12 for 2 min at 37° C.

The following compounds exhibit IC50 values of less than 10 mM in theHuman VR1 Capsaicin Antagonist Assay:

-   (2S)-8-({2-{[(1S)-1-(4-fluorophenyl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;-   (5R)-N-[2-(6-[(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yl)oxy]-2-{[(1S)-2-methoxy-1-methylethyl]amino}pyrimidin-4-yl)-5-(trifluoromethyl)phenyl]-5-methyl-L-prolinamide;-   1-{4-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}piperidine-4-carboxylic    acid;-   2-{[4-(4-tert-butylphenyl)-6-(2,3-dihydro-1,4-benzodioxin-6-ylamino)pyrimidin-2-yl]amino}ethanol;-   3-amino-5-({2-({[(2R)-1-isobutylpiperidin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-({2-({[(2R)-1-neopentylpiperidin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-({2-({[(2S)-1-(cyclopropylmethyl)piperidin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-({2-({[(2S)-1-isobutylpiperidin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-({2-({[(2S)-1-isobutylpiperidin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-({2-({2-[(2S)-2-methylpiperidin-1-yl]ethyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-({2-(4-amino-3-fluorophenyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-({2-(4-isobutylpiperazin-1-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-({2-(isobutyl    {[(2S)-1-isobutylpiperidin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-({2-[(2-methyl-2-morpholin-4-ylpropyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-({2-[(2-morpholin-4-ylethyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-({2-[(pyridin-3-ylmethyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-({2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-({2-[4-(methylsulfonyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-({2-{[(1R)-1-(4-fluorophenyl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-({2-{[(1R)-2-methoxy-1-methylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-({2-{[(1S)-1-pyridin-2-ylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-({2-{[(1S)-1-pyridin-3-ylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-({2-{[(1S)-2-methoxy-1-methylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-({2-piperazin-1-yl-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-({6-{4-[(1R)-1-(4-fluorophenyl)ethyl]piperazin-1-yl}-2-[(2-methoxyethyl)amino]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;-   3-amino-5-[(6-[(3S)-3-isobutyl-4-(2,2,2-trifluoroethyl)piperazin)-yl]-2-{[(1S)-2-methoxy-1-methylethyl]amino}pyrimidin-4-yl)oxy]quinoxalin-2(1H)-one;-   3-amino-5-[(6-[2-[(3,4-dimethoxybenzyl)amino]-6-(trifluoromethyl)pyridin-3-yl]-2-{[(1S)-2-methoxy-1-methylethyl]amino}pyrimidin-4-yl)oxy]quinoxalin-2(1H)-one;-   3-amino-5-[(6-[2-amino-4-(trifluoromethyl)phenyl]-2-{[(1S)-2-methoxy-1-methylethyl]amino}pyrimidin-4-yl)oxy]quinoxalin-2(1H)-one;-   3-amino-5-[(6-[2-amino-6-(trifluoromethyl)pyridin-3-yl]-2-{[(1S)-2-methoxy-1-methylethyl]amino}pyrimidin-4-yl)oxy]quinoxalin-2(1H)-one;-   3-amino-5-[(6-{4-[(1R)-1-(4-fluorophenyl)ethyl]piperazin-1-yl}-2-{[(1S)-2-methoxy-1-methylethyl]amino}pyrimidin-4-yl)oxy]quinoxalin-2(1H)-one;-   3-amino-5-[(6-{4-[(1R)-1-(4-fluorophenyl)ethyl]piperazin-1-yl}-2-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}pyrimidin-4-yl)oxy]quinoxalin-2(1H)-one;-   3-amino-5-[(6-{4-[(1S)-1-(4-fluorophenyl)ethyl]piperazin-1-yl}-2-{[(1S)-2-methoxy-1-methylethyl]amino}pyrimidin-4-yl)oxy]quinoxalin-2(1H)-one;-   4-({2-({2-[(2S)-2-methylpiperidin-1-yl]ethyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;-   4-({2-(1H-benzimidazol-2-ylamino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;-   4-({2-(2-piperidin-1-ylethyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;-   4-({2-(aminomethyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;-   4-({2-[(1-ethylpiperidin-3-yl)oxy]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;-   4-({2-[(2-methyl-2-morpholin-4-ylpropyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;-   4-({2-[(2-methyl-2-piperidin-1-ylpropyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;-   4-({2-[2-(2,5-dimethylpyrrolidin-1-yl)ethyl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;-   4-({2-[2-(tert-butylamino)ethyl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;-   4-({2-{[(1R)-1-(3-fluorophenyl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;-   4-({2-{[(1R)-1-(4-fluorophenyl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;-   4-({2-{[(1R)-1-pyridin-2-ylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;-   4-({2-{[(1S)-1-cyclohexylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;-   4-({2-{[(1S)-2-methoxy-1-methylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;-   4-({2-{[2-(4,4-difluoropiperidin-1-yl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;-   4-({2-pyridin-4-yl-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;-   6-(4-tert-butylphenyl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-methylpiperazin-1-yl)pyrimidin-4-amine;-   6-(4-tert-butylphenyl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methoxypyrimidin-4-amine;-   6-(4-tert-butylphenyl)-N˜4˜-(2,3-dihydro-1,4-benzodioxin-6-yl)-N˜2˜-(2-morpholin-4-ylethyl)pyrimidine-2,4-diamine;-   6-(4-tert-butylphenyl)-N˜4˜-(2,3-dihydro-1,4-benzodioxin-6-yl)-N˜2˜-[2-(dimethylamino)ethyl]pyrimidine-2,4-diamine;-   6-(4-tert-butylphenyl)-N˜4˜-(2,3-dihydro-1,4-benzodioxin-6-yl)-N˜2˜-(2-pyrrolidin-1-ylethyl)pyrimidine-2,4-diamine;-   8-({2-({[(2R)-1-isobutylpiperidin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinolin-2-amine;-   8-({2-{[1-(4-fluorophenyl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinolin-2-amine;    IUPAC Name;-   N-[4-({2-({[(2R)-1-(cyclopropylmethyl)piperidin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-({[(2R)-4-isobutylmorpholin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-({[(2R)-4-isopropylmorpholin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-({[(2S)-1-isobutylpiperidin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-({[(2S)-1-isobutylpyrrolidin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-({[(2S)-4-(cyclopropylmethyl)morpholin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-({[(3R)-1-(cyclopropylmethyl)piperidin-3-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-({[(3R)-1-isobutylpiperidin-3-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-({1-[(2S)-1-benzylpyrrolidin-2-yl]-1-methylethyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-({2-[(2S)-2-methylpiperidin-1-yl]ethyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-(1,2,3,6-tetrahydropyridin-4-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-(1H-benzimidazol-2-ylamino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-(1-isopropylpiperidin-4-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-(1-methyl-1H-pyrrol-2-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-(2-morpholin-4-ylethyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-(2-piperidin-1-ylethyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-(2-pyrrolidin-1-ylethyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-(4-hydroxypiperidin-1-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-(4-isobutylpiperazin-1-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-(4-isopropylpiperazin-1-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-(hydroxymethyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-(piperidin-1-ylmethyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-[(1-cyclopropylethyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-[(2-amino-2-methylpropyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-[(2-methyl-2-morpholin-4-ylpropyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-[(2-methyl-2-piperidin-1-ylpropyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-[(2-morpholin-4-ylethyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-[(3R)-4-isobutyl-3-methylpiperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-[(3R)-4-isopropyl-3-methylpiperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-[(3S)-3-hydroxypiperidin-1-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-[(3S)-3-methylpiperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-[(pyridin-2-ylmethyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-[(pyridin-3-ylmethyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-[(tetrahydrofuran-2-ylmethyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-[2-(2,5-dimethylpyrrolidin-1-yl)ethyl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-[2-(2-ethylpiperidin-1-yl)ethyl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-[2-(4-fluoropiperidin-1-yl)ethyl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-[2-(tert-butylamino)ethyl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-[3-(diethylamino)pyrrolidin-1-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-[3-(hydroxymethyl)pyridin-4-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-[3-(pyrrolidin-1-ylmethyl)pyridin-4-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{[(1R)-1-(2-furyl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{[(1R)-1-(3-fluorophenyl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{[(1R)-1-(4-fluorophenyl)ethyl]oxy}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{[(1R)-1-cyclohexylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{[(1R)-1-pyridin-2-ylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{[(1R)-1-pyridin-3-ylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{[(1S)-1-(4-fluorophenyl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{[(1S)-1-cyclohexylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{[(1S)-2-(dimethylamino)-1-methylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{[(1S)-2-hydroxy-1-methylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{[(1S)-2-methoxy-1-methylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{[(2R)-piperidin-2-ylmethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{[(2S)-morpholin-2-ylmethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{[(2S)-pyrrolidin-2-ylmethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{[(3R)-piperidin-3-ylmethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{[2-(1H-imidazol-5-yl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{[2-(4,4-difluoropiperidin-1-yl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{[2-(diisopropylamino)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{[2-(methylsulfonyl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{2-[(3R)-3-fluoropiperidin-1-yl]ethyl}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-{4-[(1R)-1-(4-fluorophenyl)ethyl]piperazin-1-yl}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-cyano-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-piperazin-1-yl-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-pyrazin-2-yl-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-pyridin-2-yl-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-pyridin-3-yl-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-[4-({2-pyridin-4-yl-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;-   N-{3-[({4-[(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yl)oxy]-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}amino)methyl]phenyl}methanesulfonamide;-   N-{4-[(6-[4-(trifluoromethyl)phenyl]-2-{2-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}pyrimidin-4-yl)oxy]-1,3-benzothiazol-2-yl}acetamide;-   N-{4-[(6-{4-[(1R)-1-(4-fluorophenyl)ethyl]piperazin-1-yl}-2-{[(2S)-tetrahydrofuran-2-ylmethyl]amino}pyrimidin-4-yl)oxy]-1,3-benzothiazol-2-yl}acetamide;-   N˜1˜-{4-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}-N˜2˜-,N˜2˜-dimethylglycinamide;    Structure possibly contains peptides which are not supported in    current version!;-   tert-butyl    (2R)-2-[({4-[(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yl)oxy]-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}amino)methyl]piperidine-1-carboxylate;-   tert-butyl    (2R)-2-[({4-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}amino)methyl]piperidine-1-carboxylate;-   tert-butyl    (2R)-2-[({4-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}amino)methyl]morpholine-4-carboxylate;-   tert-butyl    (2S)-2-[({4-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}amino)methyl]pyrrolidine-1-carboxylate;-   tert-butyl    (2S)-4-(6-[(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yl)oxy]-2-{[(1S)-2-methoxy-1-methylethyl]amino}pyrimidin-4-yl)-2-isobutylpiperazine-1-carboxylate;-   tert-butyl    (3R)-3-[({4-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}amino)methyl]piperidine-1-carboxylate;-   tert-butyl    2-(6-[(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yl)oxy]-2-{[(1S)-2-methoxy-1-methylethyl]amino}pyrimidin-4-yl)-5-(trifluoromethyl)phenylcarbamate;-   tert-butyl    4-{4-[(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yl)oxy]-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}-2-fluorophenylcarbamate;-   tert-butyl    4-{4-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}-3,6-dihydropyridine-1(2H)-carboxylate;    and-   tert-butyl    4-{4-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}piperazine-1-carboxylate.    Acid Antagonist Assay:

Compounds are pre-incubated with E-19 DRG cells for 2 minutes prior toaddition of Calcium-45 in 30 mM Hepes/Mes buffer (Final Assay pH 5) andthen left for an additional 2 minutes prior to compound washout. Final45Ca (Amersham CES3-2 mCi) at 10 μCi/ML.

Agonist Assay:

Compounds are incubated with E-19 DRG cells for 2 minutes in thepresence of Calcium-45 prior to compound washout. Final ⁴⁵Ca²⁺ (AmershamCES3-2 mCi) at 10 μCi/mL.

Compound Washout and Analysis:

Assay plates are washed using an ELX405 plate washer (Bio-TekInstruments Inc.) immediately after functional assay. Wash 3× with PBSMg2+/Ca2+ free, 0.1 mg/mL BSA. Aspirate between washes. Read platesusing a MicroBeta Jet (Wallac Inc.). Compound activity is thencalculated using appropriate computational algorithms.

⁴⁵Calcium²⁺ Assay Protocol

Compounds may be assayed using Chinese Hamster Ovary cell lines stablyexpressing either human VR1 or rat VR1 under a CMV promoter. Cells canbe cultured in Growth Medium, routinely passaged at 70% confluency usingtrypsin and plated in the assay plate 24 hours prior to compoundevaluation.

Possible Growth Medium:

-   DMEM, high glucose (Gibco 11965-084).-   10% Dialyzed serum (Hyclone SH30079.03).-   1× Non-Essential Amino Acids (Gibco 11140-050).-   1× Glutamine-Pen-Strep (Gibco 10378-016).-   Geneticin, 450 μg/mL (Gibco 10131-035).

Compounds can be diluted in 100% DMSO and tested for activity overseveral log units of concentration [40 μM-2 pM]. Compounds may befurther diluted in HBSS buffer (pH 7.4) 0.1 mg/mL BSA, prior toevaluation. Final DMSO concentration in assay would be 0.5%. Each assayplate can be controlled with a buffer only and a known antagonistcompound (either capsazepine or one of the described VR1 antagonists).

Activation of VR1 can be achieved in these cellular assays using eithera capsaicin stimulus (ranging from 0.1-1 μM) or by an acid stimulus(addition of 3 mM Hepes/Mes buffered at pH 4.1). Compounds may alsotested in an assay format to evaluate their agonist properties at VR1.

Capsaicin Antagonist Assay:

Compounds may be pre-incubated with cells (expressing either human orrat VR1) for 2 minutes prior to addition of Calcium-45 and Capsaicin andthen left for an additional 2 minutes prior to compound washout.Capsaicin (0.5 nM) can be added in HAM's F12, 0.1 mg/mL BSA, 15 mM Hepesat pH 7.4. Final ⁴⁵Ca (Amersham CES3-2 mCi) at 10 μCi/mL.

Acid Antagonist Assay:

Compounds can be pre-incubated with cells (expressing either human orrat VR1) for 2 minutes prior to addition of Calcium-45 in 30 mMHepes/Mes buffer (Final Assay pH 5) and then left for an additional 2minutes prior to compound washout. Final ⁴⁵Ca (Amersham CES3-2 mCi) at10 μCi/mL.

Agonist Assay:

Compounds can be incubated with cells (expressing either human or ratVR1) for 2 minutes in the presence of Calcium-45 prior to compoundwashout. Final ⁴⁵Ca (Amersham CES3-2 mCi) at 10 μCi/mL.

Compound Washout and Analysis:

Assay plates can be washed using an ELX405 plate washer (Bio-TekInstruments Inc.) immediately after functional assay. One can wash 3×with PBS Mg2+/Ca²+ free, 0.1 mg/mL BSA, aspirating between washes.Plates may be read using a MicroBeta Jet (Wallac Inc.). Compoundactivity may then calculated using appropriate computational algorithms.

Useful nucleic acid sequences and proteins may be found in U.S. Pat.Nos. 6,335,180, 6,406,908 and 6,239,267, herein incorporated byreference in their entirety.

For the treatment of vanilloid-receptor-diseases, such as acute,inflammatory and neuropathic pain, dental pain, general headache,migraine, cluster headache, mixed-vascular and non-vascular syndromes,tension headache, general inflammation, arthritis, rheumatic diseases,osteoarthritis, inflammatory bowel disorders, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, the compounds of the present invention may be administeredorally, parentally, by inhalation spray, rectally, or topically indosage unit formulations containing conventional pharmaceuticallyacceptable carriers, adjuvants, and vehicles. The term parenteral asused herein includes, subcutaneous, intravenous, intramuscular,intrasternal, infusion techniques or intraperitoneally.

Treatment of diseases and disorders herein is intended to also includethe prophylactic administration of a compound of the invention, apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) believed to be in need of preventative treatment, such as, forexample, pain, inflammation and the like.

The dosage regimen for treating vanilloid-receptor-mediated diseases,cancer, and/or hyperglycemia with the compounds of this invention and/orcompositions of this invention is based on a variety of factors,including the type of disease, the age, weight, sex, medical conditionof the patient, the severity of the condition, the route ofadministration, and the particular compound employed. Thus, the dosageregimen may vary widely, but can be determined routinely using standardmethods. Dosage levels of the order from about 0.01 mg to 30 mg perkilogram of body weight per day, preferably from about 0.1 mg to 10mg/kg, more preferably from about 0.25 mg to 1 mg/kg are useful for allmethods of use disclosed herein.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals.

For oral administration, the pharmaceutical composition may be in theform of, for example, a capsule, a tablet, a suspension, or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a given amount of the active ingredient. For example,these may contain an amount of active ingredient from about 1 to 2000mg, preferably from about 1 to 500 mg, more preferably from about 5 to150 mg. A suitable daily dose for a human or other mammal may varywidely depending on the condition of the patient and other factors, but,once again, can be determined using routine methods.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg,and more preferably from about 0.25 mg to 1 mg/kg.

Injectable preparations, such as sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known areusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

A suitable topical dose of active ingredient of a compound of theinvention is 0.1 mg to 150 mg administered one to four, preferably oneor two times daily. For topical administration, the active ingredientmay comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight ofthe formulation, although it may comprise as much as 10% w/w, butpreferably not more than 5% w/w, and more preferably from 0.1% to 1% ofthe formulation.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose.

For administration, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate for the indicated routeof administration. The compounds may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, stearic acid, talc,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, acacia, gelatin, sodium alginate,polyvinyl-pyrrolidine, and/or polyvinyl alcohol, and tableted orencapsulated for conventional administration. Alternatively, thecompounds of this invention may be dissolved in saline, water,polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil,cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.Other adjuvants and modes of administration are well known in thepharmaceutical art. The carrier or diluent may include time delaymaterial, such as glyceryl monostearate or glyceryl distearate alone orwith a wax, or other materials well known in the art.

The pharmaceutical compositions may be made up in a solid form(including granules, powders or suppositories) or in a liquid form(e.g., solutions, suspensions, or emulsions). The pharmaceuticalcompositions may be subjected to conventional pharmaceutical operationssuch as sterilization and/or may contain conventional adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers, buffers etc.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting, sweetening,flavoring, and perfuming agents.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or non-racemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, e.g., by formationof diastereoisomeric salts, by treatment with an optically active acidor base. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting compoundsof the invention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using active starting materials.These isomers may be in the form of a free acid, a free base, an esteror a salt.

Likewise, the compounds of this invention may exist as isomers, that iscompounds of the same molecular formula but in which the atoms, relativeto one another, are arranged differently. In particular, the alkylenesubstituents of the compounds of this invention, are normally andpreferably arranged and inserted into the molecules as indicated in thedefinitions for each of these groups, being read from left to right.However, in certain cases, one skilled in the art will appreciate thatit is possible to prepare compounds of this invention in which thesesubstituents are reversed in orientation relative to the other atoms inthe molecule. That is, the substituent to be inserted may be the same asthat noted above except that it is inserted into the molecule in thereverse orientation. One skilled in the art will appreciate that theseisomeric forms of the compounds of this invention are to be construed asencompassed within the scope of the present invention.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. The salts include, but are notlimited to, the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methansulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 2-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids that may be employed to from pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

Also encompassed in the scope of the present invention arepharmaceutically acceptable esters of a carboxylic acid or hydroxylcontaining group, including a metabolically labile ester or a prodrugform of a compound of this invention. A metabolically labile ester isone which may produce, for example, an increase in blood levels andprolong the efficacy of the corresponding non-esterified form of thecompound. A prodrug form is one which is not in an active form of themolecule as administered but which becomes therapeutically active aftersome in vivo activity or biotransformation, such as metabolism, forexample, enzymatic or hydrolytic cleavage. For a general discussion ofprodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examplesof a masked carboxylate anion include a variety of esters, such as alkyl(for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl),aralkyl (for example, benzyl, p-methoxybenzyl), andalkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have beenmasked as arylcarbonyloxymethyl substituted derivatives which arecleaved by esterases in vivo releasing the free drug and formaldehyde(Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidicNH group, such as imidazole, imide, indole and the like, have beenmasked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs,Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.EP 039,051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-basehydroxamic acid prodrugs, their preparation and use. Esters of acompound of this invention, may include, for example, the methyl, ethyl,propyl, and butyl esters, as well as other suitable esters formedbetween an acidic moiety and a hydroxyl containing moiety. Metabolicallylabile esters, may include, for example, methoxymethyl, ethoxymethyl,iso-propoxymethyl, α-methoxyethyl, groups such asα-((C₁-C₄)alkyloxy)ethyl, for example, methoxyethyl, ethoxyethyl,propoxyethyl, iso-propoxyethyl, etc.; 2-oxo-1,3-dioxolen-4-ylmethylgroups, such as 5-methyl-2-oxo-1,3,dioxolen-4-ylmethyl, etc.; C₁-C₃alkylthiomethyl groups, for example, methylthiomethyl, ethylthiomethyl,isopropylthiomethyl, etc.; acyloxymethyl groups, for example,pivaloyloxymethyl, α-acetoxymethyl, etc.; ethoxycarbonyl-1-methyl; orα-acyloxy-α-substituted methyl groups, for example α-acetoxyethyl.

Further, the compounds of the invention may exist as crystalline solidswhich can be crystallized from common solvents such as ethanol,N,N-dimethyl-formamide, water, or the like. Thus, crystalline forms ofthe compounds of the invention may exist as polymorphs, solvates and/orhydrates of the parent compounds or their pharmaceutically acceptablesalts. All of such forms likewise are to be construed as falling withinthe scope of the invention.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are given at the same time or differenttimes, or the therapeutic agents can be given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A compound having the structure:

or any pharmaceutically-acceptable salt or hydrate thereof, wherein: Jis NH, O or S; X is N or C(R²); Y is N or C(R²), wherein at least one ofX and Y is N; n is independently, at each instance, 0, 1 or 2; R¹ is asaturated, partially saturated or unsaturated 5-, 6- or 7-memberedmonocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 atoms selected from N, O and S, wherein theavailable carbon atoms of the ring are substituted by 0, 1 or 2 oxo orthioxo groups, wherein the ring is substituted by 1, 2 or 3 substituentsindependently selected from R^(e), R^(g), R^(c), halo, nitro, cyano,R^(i), —OR^(i), —OC₂₋₆alkylNR^(a)R^(i), —OC₂₋₆alkylOR^(i), —NR^(a)R^(i),—NR^(f)C₂₋₆alkylNR^(a)R^(i), —NR^(f)C₂₋₆alkylOR^(i), —CO₂R^(i),—C(═O)R^(i), —C(═O)NR^(a)R^(i), —NR^(f)C(═O)R^(i),—NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i), —C₁₋₈alkylOR^(i),—C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i), —S(═O)₂NR^(a)R^(i),—NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(e), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I; R²is, independently, in each instance, R^(d), halo, C₁₋₈alkyl substitutedby 0, 1 or 2 substituents selected from R^(d), halo, —(CH₂)_(n)phenylsubstituted by 0, 1, 2 or 3 substituents independently selected fromR^(d) and halo, or a saturated, partially saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, wherein no more than 2 of thering members are O or S, wherein the heterocycle is optionally fusedwith a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents independently selected fromR^(d) and halo; R³is (A) C₁₋₈alkyl substituted by 1, 2 or 3 substituentsindependently selected from halo, nitro, cyano, —OR^(i),—OC₂₋₆alkylNR^(a)R^(i), —OC₂₋₆alkylOR^(i), —NR^(a)R^(i),—NR^(f)C₂₋₆alkylNR^(a)R^(i), —NR^(f)C₂₋₆alkylOR^(i), —CO₂R^(i),—C(═O)R^(i), —C(═O)NR^(a)R^(i), —NR^(f)C(═O)R^(i),—NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i), —C₁₋₈alkylOR^(i),—C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i), —S(═O)₂NR^(a)R^(i),—NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(f), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), —CO₂R^(e),—C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g), —NR^(f)C(═O)R^(e),—NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e),—C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e),—S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and —OC(═O)NR^(a)R^(f), andadditionally substituted by 0, 1 or 2 R^(i) groups, and additionallysubstituted by 0, 1, 2, 3, 4 or 5 substituents independently selectedfrom Br, Cl, F and I; or (B) a saturated, partially saturated orunsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected fromN, O and S, wherein the available carbon atoms of the ring aresubstituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring issubstituted by 0, 1, 2 or 3 substituents independently selected fromR^(e), R^(h), halo, nitro, cyano, —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I; or(C) —N(R^(a))—C₁₋₈alkyl, wherein the C₁₋₈alkyl is substituted by 1, 2 or3 substituents independently selected from R^(h), halo, nitro, cyano,R^(i), —OR^(i), —OC₂₋₆alkylNR^(a)R^(i), —OC₂₋₆alkylOR^(i), —NR^(a)R^(i),—NR^(f)C₂₋₆alkylNR^(a)R^(i), —NR^(f)C₂₋₆alkylOR^(i), —CO₂R^(i),—C(═O)R^(i), —C(═O)NR^(a)R^(i), —NR^(f)C(═O)R^(i),—NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i), C₁₋₈alkylOR^(i),C₁₋₆alkylNR^(i), —S(═O)_(n)R^(i), —S(═O)₂NR^(a)R^(i),—NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)r^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and additionally substituted by 0, 1, 2, 3, 4 or 5substituents independently selected from Br, Cl, F and I; or (D)—OC₁₋₈alkyl, wherein the C₁₋₈alkyl is substituted by 1, 2 or 3substituents independently selected from R^(e), R^(h), halo, nitro,cyano, R^(i), —OR^(i), —OC₂₋₆alkylNR^(a)R^(i), —OC₂₋₆alkylOR^(i),—NR^(a)R^(i), —NR^(f)C₂₋₆alkylNR^(a)R^(i), —NR^(f)C₂₋₆alkylOR^(i),—CO₂R^(i), —C(═O)R^(i), —C(═O)NR^(a)R^(i), —NR^(f)C(═O)R^(i),—NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i), C₁₋₈alkylOR^(i),—C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i), —S(═O)₂NR^(a)R^(i),—NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O) NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and additionally substituted by 0, 1, 2, 3, 4 or 5substituents independently selected from Br, Cl, F and I; or (E)C₄₋₈alkyl, cyano, —OC₃₋₈alkyl, —OR^(i), —SR^(i), —N(R^(a))R^(i),—NHC₄₋₈alkyl, or —N(C₁₋₈alkyl)C₄₋₈alkyl; R⁴ is a 6-, 7-, 8-, 9-, 10- or11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected fromN, O and S, wherein the available carbon atoms of the ring aresubstituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring issubstituted by 0, 1, 2 or 3 substituents independently selected fromR^(f), R^(g), R^(c), nitro, cyano, —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I;wherein R⁴ is not indazolyl; R⁵ is H or CH₃; R^(a) is independently, ateach instance, H or R^(b); R^(b) is independently, at each instance,phenyl, benzyl or C, ₁₋₆alkyl, the phenyl, benzyl and C₁₋₆alkyl beingsubstituted by 0, 1, 2 or 3 substituents selected from halo, C₁₋₄alkyl,C₁₋₃haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl;R^(c) is independently, in each instance, phenyl substituted by 0, 1 or2 groups selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(a) and—NR^(a)R^(a); or R^(c) is a saturated, partially saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3heteroatoms independently selected from N, O and S, wherein no more than2 of the ring members are O or S, wherein the heterocycle is optionallyfused with a phenyl ring, and the carbon atoms of the heterocycle aresubstituted by 0, 1 or 2 oxo or thioxo or thioxo groups, wherein theheterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(a) and—NR^(a)R^(a); R^(d) is independently in each instance selected from H,C₁₋₅alkyl, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R^(d) is a saturated, partially saturated orunsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or11-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, Oand S, wherein there are no more than 2 N atoms, wherein the ring issubstituted by 0, 1 or 2 oxo or thioxo or thioxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from R^(e), halo,cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R^(d) is C₁₋₄alkyl substituted by 0, 1, 2 or3 groups selected from C₁₋₄-haloalkyl, halo, cyano, nitro, —C(═O)R^(e),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), N(R^(a))C(═O)R^(h),═N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R , —N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a)C(═NR)^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h),—N(R^(h))S(═O)₂NR^(a)R^(f), —N(R^(a))S(═O)₂NR^(a)R^(h),—NR^(h)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(h),—NR^(h)C₂₋₆alkylOR^(f) and —NR^(a)C₂₋₆alkylOR^(h); R^(e) is,independently, in each instance, C₁₋₉alkyl or C₁₋₄alkyl(phenyl) whereineither is substituted by 0, 1, 2, 3 or 4 substituents selected fromhalo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), ═S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); and wherein theC₁₋₉alkyl is additionally substituted by 0 or 1 groups independentlyselected from R^(h) and additionally substituted by 0, 1, 2, 3, 4 or 5substituents independently selected from Br, Cl, F and I; R^(f) is,independently, in each instance, R^(e) or H; R^(g) is, independently, ineach instance, a saturated, partially saturated or unsaturated 5- or6-membered monocyclic ring containing 1, 2 or 3 atoms selected from N, Oand S, so long as the combination of O and S atoms is not greater than2, wherein the ring is substituted by 0 or 1 oxo or thioxo groups; R^(h)is, independently, in each instance, phenyl or a saturated, partiallysaturated or unsaturated 5- or 6-membered monocyclic ring containing 1,2 or 3 atoms selected from N, O and S, so long as the combination of Oand S atoms is not greater than 2, wherein the ring is substituted by 0or 1 oxo or thioxo groups, wherein the phenyl or monocycle aresubstituted by 0, 1, 2 or 3 substituents selected from halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂ alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(f), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(e),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(e), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f) and —NR^(a)C₂₋₆alkylOR^(f); and R^(i) is a saturated, partially saturated orunsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected fromN, O and S, wherein the available carbon atoms of the ring aresubstituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring issubstituted by 0, 1, 2 or 3 substituents independently selected fromR^(f), R^(g), R^(c), halo, nitro, cyano, —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(e), —C(═O) NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), C₁₋₈alkylOR^(f), C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e),—S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and —OC(═O)NR^(a)R^(f), and thering is additionally substituted by 0, 1, 2, 3, 4 or 5 substituentsindependently selected from Br, Cl, F and I.
 2. A compound according toclaim 1, wherein R¹ is phenyl substituted in the 4-position by asubstituent selected from R^(f), halo, or —OR^(e), and the phenyl isfurther substituted by 0, 1 or 2 substituents independently selectedfrom R^(f), R^(g), R^(e), halo, nitro, cyano, R^(i), —OR^(i),—OC₂₋₆alkylNR^(a)R^(i), —OC₂₋₆alkylOR^(i), —NR^(a)R^(i),—NR^(f)C₂₋₆alkylNR^(a)R^(i), —NR^(f)C₂₋₆alkylOR^(i), —CO₂R^(i),—C(═O)R^(i), —C(═O)NR^(a)R^(i), —NR^(f)C(═O)R^(i),—NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i), —C₁₋₈alkylOR^(i),—C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i), —S(═O)₂NR^(a)R^(i),—NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(e), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the phenyl is additionally substituted by 0, 1or 2 substituents independently selected from Br, Cl, F and I.
 3. Acompound according to claim 1, wherein R¹ is an unsaturated 5-, 6- or7-membered monocyclic ring containing 1, 2, 3 or 4 atoms selected fromN, O and S, wherein the available carbon atoms of the ring aresubstituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring issubstituted by 1, 2 or 3 substituents independently selected from R^(f),R^(g), R^(c), nitro, cyano, R^(i), —OR^(i), —OC₂₋₆alkylNR^(a)R^(i),—OC₂₋₆alkylOR^(i), —NR^(a)R^(i), —NR^(f)C₂₋₆alkylNR^(a)R^(i),—NR^(f)C₂₋₆alkylOR^(i), —CO₂R^(i), —C(═O)R^(i), —C(═O)NR^(a)R^(i),—NR^(f)C(═O)R^(i), —NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i),—C₁₋₈alkylOR^(i), —C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i),—S(═o)₂NR^(a)R^(i), —NR^(a)S(═o)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(e),—OR^(g), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f),—NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f),naphthyl, —CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(e), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I.
 4. Acompound according to claim 1, wherein R³ is C₁₋₈alkyl substituted by 1,2 or 3 substituents independently selected from halo, nitro, cyano,—OR^(i), —OC₂₋₆alkylNR^(a)R^(i), —OC₂₋₆alkylOR^(i), —NR^(a)R^(i),—NR^(f)C₂₋₆alkylNR^(a)R^(i), —NR^(f)C₂₋₆alkylOR^(i), —CO₂R^(i),—C(═O)R^(i), —C(═O)NR^(a)R^(i), —NR^(f)C(═O)R^(i),—NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i), —C₁₋₈alkylOR^(i),—C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i), —S(═O)₂NR^(a)R^(i),—NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(f), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), —CO₂R^(e),—C(═O)R^(e), —C(═O)NR^(a)R^(e), —C(═O)NR^(a)R^(g), —NR^(f)C(═O)R^(e),—NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e),—C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e),S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and —OC(═O)NR^(a)R^(f), andadditionally substituted by 0, 1 or 2 R^(i) groups, and additionallysubstituted by 0, 1, 2, 3, 4 or 5 substituents independently selectedfrom Br, Cl, F and I.
 5. A compound according to claim 1, wherein R³ isa saturated, partially saturated or unsaturated 5-, 6- or 7-memberedmonocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ringcontaining 0, 1, 2, 3 or 4 atoms selected from N, O and S, wherein theavailable carbon atoms of the ring are substituted by 0, 1 or 2 oxo orthioxo groups, wherein the ring is substituted by 0, 1, 2 or 3substituents independently selected from R^(e), R^(h), halo, nitro,cyano, —OR^(e), —OR^(g), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—NR^(a)R^(f), —NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f),—NR^(f)C₂₋₆alkylOR^(f), naphthyl, —CO₂R^(e), —C(═O)R^(e),—C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g), —NR^(f)C(═O)R^(e),—NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e),—C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e),—S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and —OC(═O)NR^(a)R^(f), and thering is additionally substituted by 0, 1, 2, 3, 4 or 5 substituentsindependently selected from Br, Cl, F and I.
 6. A compound according toclaim 1, wherein R³ is —N(R^(a))—C₁₋₈alkyl, wherein the C₁₋₈alkyl issubstituted by 1, 2 or 3 substituents independently selected from R^(h),halo, nitro, cyano, R^(i), —OR^(i), —OC₂₋₆alkylNR^(a)R^(i),—OC₂₋₆alkylOR^(i), —NR^(a)R^(i), —NR^(f)C₂₋₆alkylNR^(a)R^(i),—NR^(f)C₂₋₆alkylOR^(i), —CO₂R^(i), —C(═O)R^(i), —C(═O)NR^(a)R^(i),—NR^(f)C(═O)R^(i), —NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i),—C₁₋₈alkylOR^(i), —C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i),—S(═O)₂NR^(a)R^(i), —NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(e),—OR^(g), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f),—NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f),naphthyl, —CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and additionally substituted by 0, 1, 2, 3, 4 or 5substituents independently selected from Br, Cl, F and I.
 7. A compoundaccording to claim 1, wherein R³ is —OC₁₋₈alkyl, wherein the C₁₋₈alkylis substituted by 1, 2 or 3 substituents independently selected fromR^(e), R^(h), halo, nitro, cyano, R^(i), —OR₂₋₆alkylNR^(a)R^(i),—OC₂₋₆alkylNR^(a)R^(i), —OC₂₋₆alkylOR^(i), —NR^(a)R^(i),—NR^(f)C₂₋₆alkylNR^(a)R^(i), —NR^(f)C₂₋₆alkylOR^(i), —CO₂R^(i),—C(═O)R^(i), —C(═O)NR^(a)R^(i), —NR^(f)C(═O)R^(i),—NR^(f)C(═O)NR^(a)R^(i), —NR^(f)CO₂R^(i), —C₁₋₈alkylOR^(i),—C₁₋₆alkylNR^(a)R^(i), —S(═O)_(n)R^(i), —S(═O)₂NR^(a)R^(i),—NR^(a)S(═O)₂R^(i), —OC(═O)NR^(a)R^(i), —OR^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆NR^(a)R^(f), —S(═O)_(n)R^(e),—S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and —OC(═O)NR^(a)R^(f), andadditionally substituted by 0, 1, 2, 3, 4 or 5 substituentsindependently selected from Br, Cl, F and I.
 8. A compound according toclaim 1, wherein R³ is C₄₋₈alkyl, cyano, —OC₃₋₈alkyl, —OR^(i), —SR^(i),—N(R^(a))R^(i), —NHC₄₋₈alkyl, or —N(C₁₋₈alkyl)C₄₋₈alkyl.
 9. A compoundaccording to claim 1, wherein R⁴ is a partially saturated or unsaturated9-membered bicyclic ring containing 1 atom selected from O and S, and 1,2 or 3 N atoms, wherein the ring is substituted by 0, 1, 2 or 3substituents independently selected from R^(f), R^(g), R^(c), nitro,cyano, —OR^(e), —OR^(g), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—NR^(a)R^(f), —NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f),—NR^(f)C₂₋₆alkylOR^(f), naphthyl, —CO₂R^(e), —C(═O)R^(e),—C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g), —NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f),—C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f),—NR^(a)S(═O)₂R^(e) and —OC(═O)NR^(a)R^(f), and the ring is additionallysubstituted by 0, 1, 2, 3, 4 or 5 substituents independently selectedfrom Br, Cl, F and I.
 10. A compound according to claim 1, wherein R⁴ isan unsaturated 10-membered bicyclic ring containing 0, 1, 2, 3 or 4 Natoms, wherein the ring is substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(f), R^(g), R^(c), nitro, cyano, —OR^(e),—OR^(g), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f),—NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f),naphthyl, —CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and the ring is additionally substituted by 0, 1, 2,3, 4 or 5 substituents independently selected from Br, Cl, F and I. 11.A compound according to claim 1 selected from the group of:(2S)-8-({2-{[(1S)-1-(4-fluorophenyl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;(5R)-N-[2-(6-[(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yl)oxy]-2-{[(1S)-2-methoxy-1-methylethyl]amino}pyrimidin-4-yl)-5-(trifluoromethyl)phenyl]-5-methyl-L-prolinamide;1-{4-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}piperidine-4-carboxylicacid;2-{[4-(4-tert-butylphenyl)-6-(2,3-dihydro-1,4-benzodioxin-6-ylamino)pyrimidin-2-yl]amino}ethanol;3-amino-5-({2-({[(2R)-1-isobutylpiperidin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-({2-({[(2R)-1-neopentylpiperidin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-({2-({[(2S)-1-(cyclopropylmethyl)piperidin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-({2-({[(2S)-1-isobutylpiperidin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-({2-({[(2S)-1-isobutylpiperidin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-({2-({2-[(2S)-2-methylpiperidin-1-yl]ethyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-({2-(4-amino-3-fluorophenyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-({2-(4-isobutylpiperazin-1-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-({2-(isobutyl{[(2S)-1-isobutylpiperidin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-({2-[(2-methyl-2-morpholin-4-ylpropyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-({2-[(2-morpholin-4-ylethyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-({2-[(pyridin-3-ylmethyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-({2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-({2-[4-(methylsulfonyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-({2-{[(1R)-1-(4-fluorophenyl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-({2-{[(1R)-2-methoxy-1-methylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-({2-{[(1S)-1-pyridin-2-ylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-({2-{[(1S)-1-pyridin-3-ylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-({2-{[(1S)-2-methoxy-1-methylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-({2-piperazin-1-yl-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-({6-{4-[(1R)-1-(4-fluorophenyl)ethyl]piperazin-1-yl}-2-[(2-methoxyethyl)amino]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;3-amino-5-[(6-[(3S)-3-isobutyl-4-(2,2,2-trifluoroethyl)piperazin-1-yl]-2-{[(1S)-2-methoxy-1-methylethyl]amino}pyrimidin-4-yl)oxy]quinoxalin-2(1H)-one;3-amino-5-[(6-[2-[(3,4-dimethoxybenzyl)amino]-6-(trifluoromethyl)pyridin-3-yl]-2-{[(1S)-2-methoxy-1-methylethyl]amino}pyrimidin-4-yl)oxy]quinoxalin-2(1H)-one;3-amino-5-[(6-[2-amino-4-(trifluoromethyl)phenyl]-2-{[(1S)-2-methoxy-1-methylethyl]amino}pyrimidin-4-yl)oxy]quinoxalin-2(1H)-one;3-amino-5-[(6-[2-amino-6-(trifluoromethyl)pyridin-3-yl]-2-{[(1S)-2-methoxy-1-methylethyl]amino}pyrimidin-4-yl)oxy]quinoxalin-2(1H)-one;3-amino-5-[(6-{4-[(1R)-1-(4-fluorophenyl)ethyl]piperazin-1-yl}-2-{[(1S)-2-methoxy-1-methylethyl]amino}pyrimidin-4-yl)oxy]quinoxalin-2(1H)-one;3-amino-5-[(6-{4-[(1R)-1-(4-fluorophenyl)ethyl]piperazin-1-yl}-2-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}pyrimidin-4-yl)oxy]quinoxalin-2(1H)-one;3-amino-5-[(6-{4-[(1S)-1-(4-fluorophenyl)ethyl]piperazin-1-yl}-2-{[(1S)-2-methoxy-1-methylethyl]amino}pyrimidin-4-yl)oxy]quinoxalin-2(1H)-one;4-({2-({2-[(2S)-2-methylpiperidin-1-yl]ethyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;4-({2-(1H-benzimidazol-2-ylamino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;4-({2-(2-piperidin-1-ylethyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;4-({2-(aminomethyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;4-({2-[(1-ethylpiperidin-3-yl)oxy]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;4-({2-[(2-methyl-2-morpholin-4-ylpropyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;4-({2-[(2-methyl-2-piperidin-1-ylpropyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;4-({2-[2-(2,5-dimethylpyrrolidin-1-yl)ethyl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;4-({2-[2-(tert-butylamino)ethyl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;4-({2-{[(1R)-1-(3-fluorophenyl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;4-({2-{[(1R)-1-(4-fluorophenyl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;4-({2-{[(1R)-1-pyridin-2-ylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;4-({2-{[(1S)-1-cyclohexylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;4-({2-{[(1S)-2-methoxy-1-methylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;4-({2-{[2-(4,4-difluoropiperidin-1-yl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;4-({2-pyridin-4-yl-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;6-(4-tert-butylphenyl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-methylpiperazin-1-yl)pyrimidin-4-amine;6-(4-tert-butylphenyl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methoxypyrimidin-4-amine;6-(4-tert-butylphenyl)-N˜4˜-(2,3-dihydro-1,4-benzodioxin-6-yl)-N˜2˜-(2-morpholin-4-ylethyl)pyrimidine-2,4-diamine;6-(4-tert-butylphenyl)-N˜4˜-(2,3-dihydro-1,4-benzodioxin-6-yl)-N˜2˜-[2-(dimethylamino)ethyl]pyrimidine-2,4-diamine;6-(4-tert-butylphenyl)-N˜4˜-(2,3-dihydro-1,4-benzodioxin-6-yl)-N˜2˜-(2-pyrrolidin-1-ylethyl)pyrimidine-2,4-diamine;8-({2-({[(2R)-1-isobutylpiperidin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinolin-2-amine;8-({2-{[1-(4-fluorophenyl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinolin-2-amine;IUPAC Name;N-[4-({2-({[(2R)-1-(cyclopropylmethyl)piperidin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-({[(2R)-4-isobutylmorpholin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-({[(2R)-4-isopropylmorpholin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-({[(2S)-1-isobutylpiperidin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-({[(2S)-1-isobutylpyrrolidin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-({[(2S)-4-(cyclopropylmethyl)morpholin-2-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-({[(3R)-1-(cyclopropylmethyl)piperidin-3-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-({[(3R)-1-isobutylpiperidin-3-yl]methyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-({1-[(2S)-1-benzylpyrrolidin-2-yl]-1-methylethyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-({2-[(2S)-2-methylpiperidin-1-yl]ethyl}amino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-(1,2,3,6-tetrahydropyridin-4-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-(1H-benzimidazol-2-ylamino)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-(1-isopropylpiperidin-4-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-(1-methyl-1H-pyrrol-2-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-(2-morpholin-4-ylethyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-(2-piperidin-1-ylethyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-(2-pyrrolidin-1-ylethyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-(4-hydroxypiperidin-1-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-(4-isobutylpiperazin-1-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-(4-isopropylpiperazin-1-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-(hydroxymethyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-(piperidin-1-ylmethyl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-[(1-cyclopropylethyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-[(2-amino-2-methylpropyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-[(2-methyl-2-morpholin-4-ylpropyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-[(2-methyl-2-piperidin-1-ylpropyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-[(2-morpholin-4-ylethyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-[(3R)-4-isobutyl-3-methylpiperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-[(3R)-4-isopropyl-3-methylpiperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-[(3S)-3-hydroxypiperidin-1-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-[(3S)-3-methylpiperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-[(pyridin-2-ylmethyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-[(pyridin-3-ylmethyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-[(tetrahydrofuran-2-ylmethyl)amino]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-[2-(2,5-dimethylpyrrolidin-1-yl)ethyl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-[2-(2-ethylpiperidin-1-yl)ethyl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-[2-(4-fluoropiperidin-1-yl)ethyl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-[2-(tert-butylamino)ethyl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-[3-(diethylamino)pyrrolidin-1-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-[3-(hydroxymethyl)pyridin-4-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-[3-(pyrrolidin-1-ylmethyl)pyridin-4-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{[(1R)-1-(2-furyl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{[(1R)-1-(3-fluorophenyl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{[(1R)-1-(4-fluorophenyl)ethyl]oxy}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{[(1R)-1-cyclohexylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{[(1R)-1-pyridin-2-ylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{[(1R)-1-pyridin-3-ylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{[(1S)-1-(4-fluorophenyl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{[(1S)-1-cyclohexylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{[(1S)-2-(dimethylamino)-1-methylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{[(1S)-2-hydroxy-1-methylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{[(1S)-2-methoxy-1-methylethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{[(2R)-piperidin-2-ylmethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{[(2S)-morpholin-2-ylmethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{[(2S)-pyrrolidin-2-ylmethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{[(3R)-piperidin-3-ylmethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{[2-(1H-imidazol-5-yl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{[2-(4,4-difluoropiperidin-1-yl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{[2-(diisopropylamino)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{[2-(methylsulfonyl)ethyl]amino}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{2-[(3R)-3-fluoropiperidin-1-yl]ethyl}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-{4-[(1R)-1-(4-fluorophenyl)ethyl]piperazin-1-yl}-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-cyano-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-piperazin-1-yl-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-pyrazin-2-yl-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-pyridin-2-yl-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-pyridin-3-yl-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({2-pyridin-4-yl-6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-{3-[({4-[(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yl)oxy]-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}amino)methyl]phenyl}methanesulfonamide;N-{4-[(6-[4-(trifluoromethyl)phenyl]-2-{2-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}pyrimidin-4-yl)oxy]-1,3-benzothiazol-2-yl}acetamide;N-{4-[(6-{4-[(1R)-1-(4-fluorophenyl)ethyl]piperazin-1-yl}-2-{[(2S)-tetrahydrofuran-2-ylmethyl]amino}pyrimidin-4-yl)oxy]-1,3-benzothiazol-2-yl}acetamide;N˜1˜-{4-{[2-acetylamino)-1,3-benzothiazol-4-yl]oxy}-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}-N˜2˜,N˜2˜-dimethylglycinamide;Structure possibly contains peptides which are not supported in currentversion!; tert-butyl(2R)-2-[({4-[(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yl)oxy]-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}amino)methyl]piperidine-1-carboxylate;tert-butyl(2R)-2-[({4-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}amino)methyl]piperidine-1-carboxylate;tert-butyl(2R)-2-[({4-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}amino)methyl]morpholine-4-carboxylate;tert-butyl(2S)-2-[({4-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}amino)methyl]pyrrolidine-1-carboxylate;tert-butyl(2S)-4-(6-[(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yl)oxy]-2-{[(1S)-2-methoxy-1-methylethyl]amino}pyrimidin-4-yl)-2-isobutylpiperazine-1-carboxylate;tert-butyl(3R)-3-[({4-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}amino)methyl]piperidine-1-carboxylate;tert-butyl2-(6-[(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yl)oxy]-2-{[(1S)-2-methoxy-1-methylethyl]amino}pyrimidin-4-yl)-5-(trifluoromethyl)phenylcarbamate;tert-butyl4-{4-[(3-amino-2-oxo-1,2-dihydroquinoxalin-5-yl)oxy]-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}-2-fluorophenylcarbamate;tert-butyl4-{4-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}-3,6-dihydropyridine-1(2H)-carboxylate;and tert-butyl4-{4-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}piperazine-1-carboxylate;or any pharmaceutically-acceptable salts or hydrates thereof.
 12. Amethod of treating acute, inflammatory and neuropathic pain, dentalpain, general headache, migraine, cluster headache, mixed-vascular andnon-vascular syndromes, tension headache, general inflammation,arthritis, rheumatic diseases, osteoarthritis, inflammatory boweldisorders, inflammatory eye disorders, inflammatory or unstable bladderdisorders, psoriasis, skin complaints with inflammatory components,chronic inflammatory conditions, inflammatory pain and associatedhyperalgesia and allodynia, neuropathic pain and associated hyperalgesiaand allodynia, diabetic neuropathy pain, causalgia, sympatheticallymaintained pain, deafferentation syndromes, asthma, epithelial tissuedamage or dysfunction, herpes simplex, disturbances of visceral motilityat respiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, comprising the step of administering a compound according toclaim
 1. 13. A method of treating acute, inflammatory and neuropathicpain, dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, inflammatory eye disorders, inflammatoryor unstable bladder disorders, psoriasis, skin complaints withinflammatory components, chronic inflammatory conditions, inflammatorypain and associated hyperalgesia and allodynia, neuropathic pain andassociated hyperalgesia and allodynia, diabetic neuropathy pain,causalgia, sympathetically maintained pain, deafferentation syndromes,asthma, epithelial tissue damage or dysfunction, herpes simplex,disturbances of visceral motility at respiratory, genitourinary,gastrointestinal or vascular regions, wounds, burns, allergic skinreactions, pruritus, vitiligo, general gastrointestinal disorders,gastric ulceration, duodenal ulcers, diarrhea, gastric lesions inducedby necrotising agents, hair growth, vasomotor or allergic rhinitis,bronchial disorders or bladder disorders, comprising the step ofadministering a compound according to claim
 11. 14. A pharmaceuticalcomposition comprising a compound according to claim 1 and apharmaceutically-acceptable diluent or carrier.
 15. A method of making acompound according to claim 1, comprising the step of:


16. A method of making a compound according to claim 1, comprising thestep of:

wherein M is B(OH)₂, SnBu₃, ZnCl, BF₃ ⁻, or MgBr.